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Schuermans S, Quanico J, Kestens C, Vandendriessche S, Slowikowski E, Crijns ML, Pörtner N, Berghmans N, Baggerman G, Mattos MS, Proost P, Marques PE. Degradation rather than disassembly of necrotic debris is essential to enhance recovery after acute liver injury. Cell Mol Life Sci 2025; 82:190. [PMID: 40301163 PMCID: PMC12040799 DOI: 10.1007/s00018-025-05720-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2025] [Revised: 04/15/2025] [Accepted: 04/17/2025] [Indexed: 05/01/2025]
Abstract
Necrotic cell death causes loss of membrane integrity, release of intracellular contents and deposition of necrotic cell debris. Effective clearance of this debris is crucial for resolving inflammation and promoting tissue recovery. While leukocyte phagocytosis plays a major role, soluble factors in the bloodstream also contribute to debris removal. Our study examined whether enzymatic degradation or disassembly of necrotic debris enhances clearance and improves outcomes in a mouse model of drug-induced liver injury. Using intravital microscopy and on-tissue spatially-resolved microproteomics, we demonstrated that necrotic debris is more complex than anticipated, containing DNA, filamentous actin, histones, complement C3, fibrin(ogen) and plasmin(ogen), among many other components. DNase 1 treatment facilitated recovery significantly by enhancing the clearance of DNA from necrotic areas, reducing circulating nucleosomes and actin, and lowering the associated inflammatory response. However, its effect on actin and other damage-associated molecular patterns in necrotic regions was limited. Treatment with short synthetic peptides, specifically 20-amino acid-long positively charged poly L-lysine (PLK) and negatively charged poly L-glutamic acid (PLE), which displace histones from debris in vitro, did not inhibit liver injury or promote recovery. Moreover, activating plasmin to disrupt fibrin encapsulation via tissue plasminogen activator (tPa) led to increased circulating actin levels and worsening of injury parameters. These findings suggest that fibrin encapsulation is important for containing necrotic debris and that enzymatic degradation of necrotic debris is a more effective strategy to enhance tissue recovery than targeting debris disassembly.
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Affiliation(s)
- Sara Schuermans
- Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium
| | - Jusal Quanico
- Centre for Proteomics (CfP), UAntwerpen, Antwerpen, Belgium
| | - Caine Kestens
- Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium
| | - Sofie Vandendriessche
- Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium
| | - Emily Slowikowski
- Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium
| | - Maria-Laura Crijns
- Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium
| | - Noëmie Pörtner
- Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium
| | - Nele Berghmans
- Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium
| | | | - Matheus Silvério Mattos
- Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium
| | - Paul Proost
- Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium
| | - Pedro Elias Marques
- Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium.
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Livingstone EJ, Cartwright JA, Campana L, Lewis PJS, Dwyer BJ, Aird R, Man TY, Vermeren M, Rossi AG, Boulter L, Forbes SJ. Semaphorin 7a is protective through immune modulation during acetaminophen-induced liver injury. J Inflamm (Lond) 2025; 22:13. [PMID: 40114253 PMCID: PMC11927371 DOI: 10.1186/s12950-025-00429-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2024] [Accepted: 01/13/2025] [Indexed: 03/22/2025] Open
Abstract
BACKGROUND AND AIM Acetaminophen (APAP) induced acute liver injury (ALI), the leading cause acute liver failure in the western world, has limited treatment options. APAP toxicity results in massive hepatic necrosis and secondary infiltrating monocytes and neutrophils, which contribute to pathogenesis. Semaphorin 7a (Sema7a), a chemoattractant and modulator of monocytes and neutrophils, is a potential therapeutic target in other conditions, but its role in APAP-ALI is unexplored. METHODS Wild-type (WT) and Sema7a knockout (KO) mice were examined during APAP-ALI. Serum liver function tests, histological analysis and cellular localisation of Sema7a and its receptors, Plexin C1 and Integrin β1, were examined. Serum cytokines were quantified, tissue macrophages and neutrophils were localised, and in vivo phenotype, including phagocytosis, was assessed by immunohistochemistry and flow cytometry. RESULTS Sema7a was expressed by HNF4α + peri-necrotic hepatocytes circumferentially during APAP-ALI injury phases, and serum concentrations were increased, and correlated with hepatic injury. Sema7a KO mice had increased circulating inflammatory cytokines and significantly less hepatic F4/80 + macrophages, a cell type required for hepatic repair. Sema7a KO mice had higher necrotic area neutrophils, and increased neutrophil chemoattractant CXCL1. Without Sema7a expression, mice displayed increased necrosis and liver injury markers compared to Sema7a WT mice. Without peri-necrotic hepatocyte Sema7a expression, we also identified increased cell death and hepatic cellular stress outside of necrosis. CONCLUSION We have identified a novel protective role of Sema7a during injury phases of APAP-ALI. Without peri-necrotic hepatocyte Sema7a expression and secretion, there is increased inflammation, time specific worsened hepatic necrosis and increased hepatic cell stress and death outside of the necrotic zone.
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Affiliation(s)
- Eilidh J Livingstone
- Centre for Regenerative Medicine, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, UK
| | - Jennifer A Cartwright
- Centre for Inflammation Research, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, UK.
- The Royal (Dick) School of Veterinary Studiesand Theaq , Roslin Institute, University of Edinburgh, Edinburgh, UK.
| | - Lara Campana
- Centre for Regenerative Medicine, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, UK
| | - Philip J Starkey Lewis
- Centre for Regenerative Medicine, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, UK
| | - Benjamin J Dwyer
- Centre for Regenerative Medicine, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, UK
| | - Rhona Aird
- Centre for Regenerative Medicine, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, UK
| | - Tak Yung Man
- Centre for Regenerative Medicine, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, UK
| | - Matthieu Vermeren
- Centre for Regenerative Medicine, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, UK
| | - Adriano Giorgio Rossi
- Centre for Inflammation Research, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, UK
| | - Luke Boulter
- MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, EH4 2XU, UK
| | - Stuart John Forbes
- Centre for Regenerative Medicine, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, UK
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Li L, Jiao Q, Yang Q, Lu H, Zhou X, Zhang Q, Zhang F, Li H, Tian Z, Zeng Z. A bladder-blood immune barrier constituted by suburothelial perivascular macrophages restrains uropathogen dissemination. Immunity 2025; 58:568-584.e6. [PMID: 40015270 DOI: 10.1016/j.immuni.2025.02.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Revised: 09/29/2024] [Accepted: 02/03/2025] [Indexed: 03/01/2025]
Abstract
Urinary tract infections (UTIs) predominantly occur in the bladder and can potentially progress into life-threatening sepsis if uropathogens spread unconstrainedly into the bloodstream. Here, we identified a subset of suburothelial perivascular macrophages (suPVMs) in the bladder that exerted a pivotal barrier function to prevent systemic bacterial dissemination during acute cystitis. During the initial phase of uropathogenic Escherichia coli (UPEC) infection, suPVMs actively captured UPEC invading the laminal propria and maintained the integrity of inflamed vessels. They subsequently underwent METosis to expel macrophage extracellular DNA traps (METs) into the urothelium to sequester bacteria within this avascular compartment. Matrix metallopeptidase-13 was released along with METs to promote neutrophil transuroepithelial migration. Replenished suPVMs from monocytes following a prior infection were functionally competent to confer protection against recurrent UTIs. Our study thus uncovers a bladder-blood immune barrier in restraining uropathogen dissemination, which could have implications for the prevention and treatment of urosepsis.
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Affiliation(s)
- Lu Li
- National Key Laboratory of Immune responses and Immunotherapy, Department of Oncology, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei 230001, China
| | - Qiancheng Jiao
- National Key Laboratory of Immune responses and Immunotherapy, Department of Oncology, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei 230001, China; Center for Advanced Interdisciplinary Science and Biomedicine of IHM, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China
| | - Qianqian Yang
- Center for Advanced Interdisciplinary Science and Biomedicine of IHM, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China
| | - Haisen Lu
- Center for Advanced Interdisciplinary Science and Biomedicine of IHM, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China
| | - Xia Zhou
- National Key Laboratory of Immune responses and Immunotherapy, Department of Oncology, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei 230001, China; Center for Advanced Interdisciplinary Science and Biomedicine of IHM, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China
| | - Qing Zhang
- Center for Advanced Interdisciplinary Science and Biomedicine of IHM, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China
| | - Futing Zhang
- Center for Advanced Interdisciplinary Science and Biomedicine of IHM, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China
| | - Hai Li
- Center for Advanced Interdisciplinary Science and Biomedicine of IHM, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China
| | - Zhigang Tian
- Center for Advanced Interdisciplinary Science and Biomedicine of IHM, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China
| | - Zhutian Zeng
- National Key Laboratory of Immune responses and Immunotherapy, Department of Oncology, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei 230001, China; Center for Advanced Interdisciplinary Science and Biomedicine of IHM, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China.
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Qian Y, Zhao J, Wu H, Kong X. Innate immune regulation in inflammation resolution and liver regeneration in drug-induced liver injury. Arch Toxicol 2025; 99:115-126. [PMID: 39395921 DOI: 10.1007/s00204-024-03886-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2024] [Accepted: 10/02/2024] [Indexed: 10/14/2024]
Abstract
Drug-induced liver injury (DILI) is an acute liver injury that poses a significant threat to human health. In severe cases, it can progress into chronic DILI or even lead to liver failure. DILI is typically caused by either intrinsic hepatotoxicity or idiosyncratic metabolic or immune responses. In addition to the direct damage drugs inflict on hepatocytes, the immune responses and liver inflammation triggered by hepatocyte death can further exacerbate DILI. Initially, we briefly discussed the differences in immune cell activation based on the type of liver cell death (hepatocytes, cholangiocytes, and LSECs). We then focused on the role of various immune cells (including macrophages, monocytes, neutrophils, dendritic cells, liver sinusoidal endothelial cells, eosinophils, natural killer cells, and natural killer T cells) in both the liver injury and liver regeneration stages of DILI. This article primarily reviews the role of innate immune regulation mediated by these immune cells in resolving inflammation and promoting liver regeneration during DILI, as well as therapeutic approaches targeting these immune cells for the treatment of DILI. Finally, we discussed the activation and function of liver progenitor cells (LPCs) during APAP-induced massive hepatic necrosis and the involvement of chronic inflammation in DILI.
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Affiliation(s)
- Yihan Qian
- Central Laboratory, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai, China
| | - Jie Zhao
- Department of Liver Surgery, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Hailong Wu
- Shanghai Key Laboratory of Molecular Imaging, Collaborative Innovation Center for Biomedicines, Shanghai University of Medicine and Health Sciences, Shanghai, China.
| | - Xiaoni Kong
- Central Laboratory, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai, China.
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Vandendriessche S, Mattos MS, Bialek EL, Schuermans S, Proost P, Marques PE. Complement activation drives the phagocytosis of necrotic cell debris and resolution of liver injury. Front Immunol 2024; 15:1512470. [PMID: 39759517 PMCID: PMC11696981 DOI: 10.3389/fimmu.2024.1512470] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Accepted: 11/29/2024] [Indexed: 01/07/2025] Open
Abstract
Cells die by necrosis due to excessive chemical or thermal stress, leading to plasma membrane rupture, release of intracellular components and severe inflammation. The clearance of necrotic cell debris is crucial for tissue recovery and injury resolution, however, the underlying mechanisms are still poorly understood, especially in vivo. This study examined the role of complement proteins in promoting clearance of necrotic cell debris by leukocytes and their influence on liver regeneration. We found that independently of the type of necrotic liver injury, either acetaminophen (APAP) overdose or thermal injury, complement proteins C1q and (i)C3b were deposited specifically on necrotic lesions via the activation of the classical pathway. Importantly, C3 deficiency led to a significant accumulation of necrotic debris and impairment of liver recovery in mice, which was attributed to decreased phagocytosis of debris by recruited neutrophils in vivo. Monocytes and macrophages also took part in debris clearance, although the necessity of C3 and CD11b was dependent on the specific type of necrotic liver injury. Using human neutrophils, we showed that absence of C3 or C1q caused a reduction in the volume of necrotic debris that is phagocytosed, indicating that complement promotes effective debris uptake in mice and humans. Moreover, internalization of opsonized debris induced the expression of pro-resolving genes in a C3-dependent manner, supporting the notion that debris clearance favors the resolution of inflammation. In summary, complement activation at injury sites is a pivotal event for necrotic debris clearance by phagocytes and determinant for efficient recovery from tissue injury.
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Affiliation(s)
| | | | | | | | | | - Pedro Elias Marques
- Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium
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Ajiboye BO, Famusiwa CD, Oyedare DI, Julius BP, Adewole ZO, Ojo OA, Akindele AFI, Hosseinzadeh H, Brai BIC, Oyinloye BE, Vitalini S, Iriti M. Effect of Hibiscus sabdariffa L. leaf flavonoid-rich extract on Nrf-2 and HO-1 pathways in liver damage of streptozotocin-induced diabetic rats. Z NATURFORSCH C 2024:znc-2024-0182. [PMID: 39565955 DOI: 10.1515/znc-2024-0182] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2024] [Accepted: 10/30/2024] [Indexed: 11/22/2024]
Abstract
This study investigated the effects of flavonoid-rich extract from Hibiscus sabdariffa L. (Malvaceae) leaves on liver damage in streptozotocin-induced diabetic rats by evaluating various biochemical parameters, including the molecular gene expressions of Nrf-2 and HO-1 as well as histological parameters. The extract was found to significantly reduce liver damage, as evidenced by lower levels of fragmented DNA and protein carbonyl concentrations. Oxidative stress markers, including malondialdehyde (MDA) level, were also significantly (p < 0.05) decreased, while antioxidant biomarkers, like reduced glutathione (GSH), catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx), and glutathione-S-transferase (GST) were enhanced. Additionally, the extract improved the activities of key liver enzymes, including phosphatases and transaminases, and increased albumin levels. Importantly, the study demonstrated that H. sabdariffa extract effectively regulated the expression of Nrf-2 and HO-1, suggesting a significant role in mitigating liver damage. These findings highlight its potential as a therapeutic agent for liver protection in diabetic conditions.
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Affiliation(s)
- Basiru Olaitan Ajiboye
- Phytomedicine and Molecular Toxicology Research Laboratory, Department of Biochemistry, Federal University Oye-Ekiti, Oye-Ekiti, Ekiti, Nigeria
| | - Courage Dele Famusiwa
- Phytomedicine and Molecular Toxicology Research Laboratory, Department of Biochemistry, Federal University Oye-Ekiti, Oye-Ekiti, Ekiti, Nigeria
| | - Damilola Ifeoluwa Oyedare
- Phytomedicine and Molecular Toxicology Research Laboratory, Department of Biochemistry, Federal University Oye-Ekiti, Oye-Ekiti, Ekiti, Nigeria
| | - Biola Paul Julius
- Phytomedicine and Molecular Toxicology Research Laboratory, Department of Biochemistry, Federal University Oye-Ekiti, Oye-Ekiti, Ekiti, Nigeria
| | - Zainab Odunola Adewole
- Phytomedicine and Molecular Toxicology Research Laboratory, Department of Biochemistry, Federal University Oye-Ekiti, Oye-Ekiti, Ekiti, Nigeria
| | - Oluwafemi Adeleke Ojo
- Phytomedicine, Molecular Toxicology, and Computational Biochemistry Research Laboratory (PMTCB-RL), Department of Biochemistry, Bowen University, Iwo, 232101, Osun, Nigeria
| | - Ajoke Fehintola Idayat Akindele
- Department of Biosciences and Biotechnology, Environmental Management and Toxicology Unit, Faculty of Sciences, University of Medical Sciences, Ondo City, Ondo State, Nigeria
| | - Hossein Hosseinzadeh
- Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
- Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Bartholomew I C Brai
- Nutritional Biochemistry and Membrane Biochemistry, and Toxicology, Federal University Oye-Ekiti, Oye-Ekiti, Ekiti, Nigeria
| | - Babatunji Emmanuel Oyinloye
- Institute of Drug Research and Development, SE Bogoro Center, Afe Babalola University, Ado-Ekiti, Nigeria
- Phytomedicine, Biochemical Toxicology and Biotechnology Research Laboratories, Department of Biochemistry, College of Sciences, Afe Babalola University, Ado-Ekiti, Ekiti, Nigeria
- Biotechnology and Structural Biology (BSB) Group, Department of Biochemistry and Microbiology, University of Zululand, KwaDlangezwa, South Africa
| | - Sara Vitalini
- Department of Biomedical, Surgical and Dental Sciences, Università Degli Studi di Milano, Via G. Celoria 2, 20133, Milan, Italy
| | - Marcello Iriti
- Department of Biomedical, Surgical and Dental Sciences, Università Degli Studi di Milano, Via G. Celoria 2, 20133, Milan, Italy
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Xu L, Feng X, Wang D, Gao F, Feng C, Shan Q, Wang G, Yang F, Zhang J, Hou J, Sun D, Wang T. Improved Liver Intravital Microscopic Imaging Using a Film-Assisted Stabilization Method. ACS Sens 2024; 9:5284-5292. [PMID: 39228132 DOI: 10.1021/acssensors.4c01464] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/05/2024]
Abstract
Intravital microscopy (IVM) is a valuable method for biomedical characterization of dynamic processes, which has been applied to many fields such as neuroscience, oncology, and immunology. During IVM, vibration suppression is a major challenge due to the inevitable respiration and heartbeat from live animals. In this study, taking liver IVM as an example, we have unraveled the vibration inhibition effect of liquid bridges by studying the friction characteristics of a moist surface on the mouse liver. We confirmed the presence of liquid bridges on the liver through fluorescence imaging, which can provide microscale and nondestructive liquid connections between adjacent surfaces. Liquid bridges were constructed to sufficiently stabilize the liver after abdominal dissection by covering it with a polymer film, taking advantage of the high adhesion properties of liquid bridges. We further prototyped a microscope-integrated vibration-damping device with adjustable film tension to simplify the sample preparation procedure, which remarkably decreased the liver vibration. In practical application scenarios, we observed the process of liposome phagocytosis by liver Kupffer cells with significantly improved image and video quality. Collectively, our method not only provided a feasible solution to vibration suppression in the field of IVM, but also has the potential to be applied to vibration damping of precision instruments or other fields that require nondestructive ″soft″ vibration damping.
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Affiliation(s)
- Libang Xu
- School of Mechanical Engineering, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Xiaobing Feng
- School of Mechanical Engineering, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Dazhi Wang
- Key Laboratory for Micro/Nano Technology and System of Liaoning Province, Dalian University of Technology, Dalian 116024, China
| | - Fang Gao
- Department of No.1 Operating Room, Dalian Municipal Central Hospital Affiliated to Dalian University of Technology, Dalian 116024, China
| | - Chenxu Feng
- School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Qiji Shan
- Instrumental Analysis Center, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Ge Wang
- School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Fang Yang
- School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Junfeng Zhang
- Department of Medical Equipment, Ningcheng Traditional Chinese and Mongolian Medicine Hospital, Chifeng 024200, China
| | - Jingwei Hou
- School of Chemical Engineering, University of Queensland, St Lucia, QLD 4072, Australia
| | - Donglei Sun
- School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Tiesheng Wang
- Key Laboratory for Micro/Nano Technology and System of Liaoning Province, Dalian University of Technology, Dalian 116024, China
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Schuermans S, Kestens C, Marques PE. Systemic mechanisms of necrotic cell debris clearance. Cell Death Dis 2024; 15:557. [PMID: 39090111 PMCID: PMC11294570 DOI: 10.1038/s41419-024-06947-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Revised: 07/23/2024] [Accepted: 07/24/2024] [Indexed: 08/04/2024]
Abstract
Necrosis is an overarching term that describes cell death modalities caused by (extreme) adverse conditions in which cells lose structural integrity. A guaranteed consequence of necrosis is the production of necrotic cell remnants, or debris. Necrotic cell debris is a strong trigger of inflammation, and although inflammatory responses are required for tissue healing, necrotic debris may lead to uncontrolled immune responses and collateral damage. Besides local phagocytosis by recruited leukocytes, there is accumulating evidence that extracellular mechanisms are also involved in necrotic debris clearance. In this review, we focused on systemic clearance mechanisms present in the bloodstream and vasculature that often cooperate to drive the clearance of cell debris. We reviewed the contribution and cooperation of extracellular DNases, the actin-scavenger system, the fibrinolytic system and reticuloendothelial cells in performing clearance of necrotic debris. Moreover, associations of the (mis)functioning of these clearance systems with a variety of diseases were provided, illustrating the importance of the mechanisms of clearance of dead cells in the organism.
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Affiliation(s)
- Sara Schuermans
- Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium
| | - Caine Kestens
- Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium
| | - Pedro Elias Marques
- Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium.
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9
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Zeng FL, Zhang Y, Wang ZH, Zhang H, Meng XT, Wu YQ, Qian ZZ, Ding YH, Li J, Ma TT, Huang C. Neutrophil extracellular traps promote acetaminophen-induced acute liver injury in mice via AIM2. Acta Pharmacol Sin 2024; 45:1660-1672. [PMID: 38589685 PMCID: PMC11272772 DOI: 10.1038/s41401-024-01239-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Accepted: 02/06/2024] [Indexed: 04/10/2024]
Abstract
Excessive acetaminophen (APAP) can induce neutrophil activation and hepatocyte death. Along with hepatocyte dysfunction and death, NETosis (a form of neutrophil-associated inflammation) plays a vital role in the progression of acute liver injury (ALI) induced by APAP overdose. It has been shown that activated neutrophils tend to migrate towards the site of injury and participate in inflammatory processes via formation of neutrophil extracellular traps (NETs). In this study we investigated whether NETs were involved in hepatocyte injury and contributed to APAP-induced ALI progression. ALI mouse model was established by injecting overdose (350 mg/kg) of APAP. After 24 h, blood and livers were harvested for analyses. We showed that excessive APAP induced multiple programmed cell deaths of hepatocytes including pyroptosis, apoptosis and necroptosis, accompanied by significantly increased NETs markers (MPO, citH3) in the liver tissue and serum. Preinjection of DNase1 (10 U, i.p.) for two consecutive days significantly inhibited NETs formation, reduced PANoptosis and consequently alleviated excessive APAP-induced ALI. In order to clarify the communication between hepatocytes and neutrophils, we induced NETs formation in isolated neutrophils, and treated HepaRG cells with NETs. We found that NETs treatment markedly increased the activation of GSDMD, caspase-3 and MLKL, while pre-treatment with DNase1 down-regulated the expression of these proteins. Knockdown of AIM2 (a cytosolic innate immune receptor) abolished NETs-induced PANoptosis in HepaRG cells. Furthermore, excessive APAP-associated ALI was significantly attenuated in AIM2KO mice, and PANoptosis occurred less frequently. Upon restoring AIM2 expression in AIM2KO mice using AAV9 virus, both hepatic injury and PANoptosis was aggravated. In addition, we demonstrated that excessive APAP stimulated mtROS production and mitochondrial DNA (mtDNA) leakage, and mtDNA activated the TLR9 pathway to promote NETs formation. Our results uncover a novel mechanism of NETs and PANoptosis in APAP-associated ALI, which might serve as a therapeutic target.
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Affiliation(s)
- Fan-le Zeng
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China
| | - Yuan Zhang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China
| | - Zhong-Hao Wang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China
| | - Hui Zhang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China
| | - Xue-Teng Meng
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China
| | - Yi-Qin Wu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China
| | - Zhen-Zhen Qian
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China
| | - Yu-Hao Ding
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China
| | - Jun Li
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China
| | - Tao-Tao Ma
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China.
- Anhui Provincial Institute of Translational Medicine, Hefei, 230032, China.
| | - Cheng Huang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China.
- Anhui Provincial Institute of Translational Medicine, Hefei, 230032, China.
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10
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Yang Q, Wang Y, Cao G, Li X, Zhao T. Anti-sepsis effect of Xiaochaihu decoction based on the TLR4/MyD88/NF-κB signalling pathway. Heliyon 2024; 10:e26712. [PMID: 38434364 PMCID: PMC10907734 DOI: 10.1016/j.heliyon.2024.e26712] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Revised: 02/08/2024] [Accepted: 02/19/2024] [Indexed: 03/05/2024] Open
Abstract
The aims of this study were to explore the protective effect of Xiaochaihu decoction in mice with sepsis induced by intraperitoneal injection; to explore its anti-inflammatory effect on the TLR4-MyD88-NF-κB signalling pathway; and to explore the main material basis of the anti-inflammatory effect of Xiaochaihu decoction, with the aim of supplementing and expanding the associated research and providing a scientific foundation for the clinical use of the decoction. The effects of Xiaochaihu decoction on septic mice were analysed by measurements of white blood cells (WBC) and Platelets (PLT); Nitric Oxide (NO) level in serum; IL-6, IL-1β and TNF-α levels in serum; RT-PCR; Haematoxylin-Eosin (HE) immunohistochemistry; western blotting (WB). The results showed the excellent in vivo anti-inflammatory effects of Xiaochaihu decoction in LPS-induced septic mice, through down regulation of the gene and protein expression of TLR4, MYD88, TRAF6, IKK, IKBα and p65 and the subsequent reduction in the release of inflammatory mediators IL-6, IL-1β, TNF-α and NO. Moreover, significant anti-septic effect was observed from high and medium doses of Xiaochaihu decoction, but not from the low dose.
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Affiliation(s)
- Qingxin Yang
- Department of Pharmacy, MianYang Orthopaedic Hospital, Mianyang, 621000, PR China
| | - Yulong Wang
- Office of Party and Government Affairs, MianYang Orthopaedic Hospital, Mianyang, 621000, PR China
| | - Gefei Cao
- Office of Party and Government Affairs, MianYang Orthopaedic Hospital, Mianyang, 621000, PR China
| | - Xiaoqing Li
- Pharmaceutical Department, MianYang Hospital of Traditional Chinese Medicine, Mianyang, 621000, PR China
| | - Tinghui Zhao
- Burn and Plastic Surgery, MianYang Central Hospital, Mianyang, 621000, PR China
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11
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Zhao J, Ghallab A, Hassan R, Dooley S, Hengstler JG, Drasdo D. A liver digital twin for in silico testing of cellular and inter-cellular mechanisms in regeneration after drug-induced damage. iScience 2024; 27:108077. [PMID: 38371522 PMCID: PMC10869925 DOI: 10.1016/j.isci.2023.108077] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Revised: 02/22/2023] [Accepted: 09/25/2023] [Indexed: 02/20/2024] Open
Abstract
This communication presents a mathematical mechanism-based model of the regenerating liver after drug-induced pericentral lobule damage resolving tissue microarchitecture. The consequence of alternative hypotheses about the interplay of different cell types on regeneration was simulated. Regeneration dynamics has been quantified by the size of the damage-induced dead cell area, the hepatocyte density and the spatial-temporal profile of the different cell types. We use deviations of observed trajectories from the simulated system to identify branching points, at which the systems behavior cannot be explained by the underlying set of hypotheses anymore. Our procedure reflects a successful strategy for generating a fully digital liver twin that, among others, permits to test perturbations from the molecular up to the tissue scale. The model simulations are complementing current knowledge on liver regeneration by identifying gaps in mechanistic relationships and guiding the system toward the most informative (lacking) parameters that can be experimentally addressed.
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Affiliation(s)
- Jieling Zhao
- Leibniz Research Centre for Working Environment and Human Factors, Technical University of Dortmund (IfADo), 44139 Dortmund, Germany
- Group SIMBIOTX, INRIA Saclay, 91120 Palaiseau, France
| | - Ahmed Ghallab
- Leibniz Research Centre for Working Environment and Human Factors, Technical University of Dortmund (IfADo), 44139 Dortmund, Germany
- Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, South Valley University, Qena 83523, Egypt
| | - Reham Hassan
- Leibniz Research Centre for Working Environment and Human Factors, Technical University of Dortmund (IfADo), 44139 Dortmund, Germany
- Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, South Valley University, Qena 83523, Egypt
| | - Steven Dooley
- Molecular Hepatology Section, Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany
| | - Jan Georg Hengstler
- Leibniz Research Centre for Working Environment and Human Factors, Technical University of Dortmund (IfADo), 44139 Dortmund, Germany
| | - Dirk Drasdo
- Leibniz Research Centre for Working Environment and Human Factors, Technical University of Dortmund (IfADo), 44139 Dortmund, Germany
- Group SIMBIOTX, INRIA Saclay, 91120 Palaiseau, France
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12
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He Z, Li W, Yuan W, He Y, Xu J, Yuan C, Zhao C, Zhang N, Fu Y, Hu X. Lactobacillus reuteri inhibits Staphylococcus aureus-induced mastitis by regulating oxytocin releasing and gut microbiota in mice. FASEB J 2024; 38:e23383. [PMID: 38197892 DOI: 10.1096/fj.202301961r] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Revised: 11/23/2023] [Accepted: 12/07/2023] [Indexed: 01/11/2024]
Abstract
Mastitis is the most frequent disease of cows and has well-recognized detrimental effects on animal wellbeing and dairy farm profitability. With the advent of the postantibiotic era, alternative antibiotic agents, especially probiotics, have received increasing attention in the treatment of mastitis. Based on research showing that Lactobacillus reuteri (L. reuteri) has anti-inflammatory effects, this study explored the protective effects and mechanisms of L. reuteri against mastitis induced by Staphylococcus aureus (S. aureus) in mice. First, mice with S. aureus-induced mastitis were orally administered L. reuteri, and the inflammatory response in the mammary gland was observed. The results showed that L. reuteri significantly inhibited S. aureus-induced mastitis. Moreover, the concentration of oxytocin (OT) and protein expression of oxytocin receptor (OTR) were measured, and inhibition of OTR or vagotomy reversed the protective effect of L. reuteri or its culture supernatant (LCS) on S. aureus-induced mastitis. In addition, in mouse mammary epithelial cells (MMECs), OT inhibited the inflammation induced by S. aureus by inhibiting the protein expression of OTR. It was suggested that L. reuteri protected against S. aureus-induced mastitis by releasing OT. Furthermore, microbiological analysis showed that the composition of the microbiota was altered, and the relative abundance of Lactobacillus was significantly increased in gut and mammary gland after treatment with L. reuteri or LCS. In conclusion, our study found the L. reuteri inhibited the mastitis-induced by S. aureus via promoting the release of OT, and treatment with L. reuteri increased the abundance of Lactobacillus in both gut and mammary gland.
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Affiliation(s)
- Zhaoqi He
- Department of Breast Surgery, China-Japan Union Hospital, Jilin University, Changchun, China
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Jilin University, Changchun, China
| | - Wenjia Li
- Department of Breast Surgery, China-Japan Union Hospital, Jilin University, Changchun, China
| | - Weijie Yuan
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Jilin University, Changchun, China
| | - Yuhong He
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Jilin University, Changchun, China
| | - Jiawen Xu
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Jilin University, Changchun, China
| | - Chongshan Yuan
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Jilin University, Changchun, China
| | - Caijun Zhao
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Jilin University, Changchun, China
| | - Naisheng Zhang
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Jilin University, Changchun, China
| | - Yunhe Fu
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Jilin University, Changchun, China
| | - Xiaoyu Hu
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Jilin University, Changchun, China
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13
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Schulte A, Groeneveld DJ, Wei Z, Hazel B, Bernard MP, Poole LG, Luyendyk JP. Neutrophil-dependent hepatic platelet accumulation and liver injury revealed by acetaminophen dose-response studies. Res Pract Thromb Haemost 2024; 8:102323. [PMID: 38404941 PMCID: PMC10883821 DOI: 10.1016/j.rpth.2024.102323] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Revised: 01/03/2024] [Accepted: 01/04/2024] [Indexed: 02/27/2024] Open
Abstract
Background Acetaminophen (APAP) overdose is a leading cause of drug-induced acute liver failure (ALF). Neutrophil activation has been associated with poor outcomes in patients with ALF and is proposed to amplify coagulation in this context. However, the precise role of neutrophils in APAP-induced liver injury is not known. Methods We used a dual antibody-mediated neutrophil depletion strategy to determine the role of neutrophils in mice challenged with different doses of APAP (300 or 600 mg/kg) that produce hepatotoxicity and ALF-like pathology. Results Flow cytometry confirmed depletion of neutrophils in whole blood prior to APAP challenge. Mice given isotype control and challenged with 300 mg/kg APAP developed marked hepatocellular necrosis and showed an increase in biomarkers of coagulation cascade activation. Neutrophil depletion (anti-Ly6G) did not affect either liver injury or coagulation activation in mice challenged with 300 mg/kg APAP. Mice given isotype control and challenged with 600 mg/kg APAP developed hepatic necrosis alongside marked hemorrhage and congestion indicative of vascular injury. Interestingly, hepatic neutrophil and platelet accumulation were increased in mice given 600 mg/kg APAP compared with those given the lower APAP dose. Neutrophil depletion significantly reduced the severity of liver necrosis in mice challenged with 600 mg/kg APAP, without significantly impacting biomarkers of coagulation activity. Notably, neutrophil depletion significantly reduced hepatic platelet accumulation in mice challenged with 600 mg/kg APAP. Conclusion The results indicate a role of neutrophils in APAP-induced liver injury that is dependent on the APAP dose and suggest involvement of neutrophil-platelet interactions in promoting hepatic injury in experimental APAP-induced ALF.
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Affiliation(s)
- Anthony Schulte
- Department of Pathobiology & Diagnostic Investigation, Michigan State University, East Lansing, Michigan, USA
| | - Dafna J. Groeneveld
- Department of Pathobiology & Diagnostic Investigation, Michigan State University, East Lansing, Michigan, USA
| | - Zimu Wei
- Department of Pathobiology & Diagnostic Investigation, Michigan State University, East Lansing, Michigan, USA
| | - Bianca Hazel
- Department of Pharmacology, Robert Wood Johnson Medical School, Rutgers University, Piscataway, New Jersey, USA
| | - Matthew P. Bernard
- Department of Pharmacology & Toxicology, Michigan State University, East Lansing, Michigan, USA
| | - Lauren G. Poole
- Department of Pharmacology, Robert Wood Johnson Medical School, Rutgers University, Piscataway, New Jersey, USA
| | - James P. Luyendyk
- Department of Pathobiology & Diagnostic Investigation, Michigan State University, East Lansing, Michigan, USA
- Department of Pharmacology & Toxicology, Michigan State University, East Lansing, Michigan, USA
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14
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Lin Y, Li Q, Liang G, Xiao N, Yang J, Yang X, Zhang H, Zhang C, Liu A. Overview of Innate Immune Cell Landscape in Liver Aging. Int J Mol Sci 2023; 25:181. [PMID: 38203352 PMCID: PMC10778796 DOI: 10.3390/ijms25010181] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2023] [Revised: 12/06/2023] [Accepted: 12/13/2023] [Indexed: 01/12/2024] Open
Abstract
Aging is a biological process with a gradual decline in functional capacity, and this process often enhances the risk of chronic disease morbidity and mortality. With advanced age, the immune system undergoes a process of remodeling that can lead to a chronic inflammatory state, termed immunosenescence and inflammaging, respectively. Immunosenescence is accompanied by changes in the number, proportion, and functional capacity of the innate immune cells. The accumulation of dysfunctional immune cells and the presence of low-grade inflammation can lead to organ damage and expedite the aging process. The liver, crucial in regulating the body's metabolism and immune function, is not exempt from these effects. Age-related modifications affect its immune function and regenerative abilities, potentially increasing the prevalence of age-related liver diseases. While aging's impact on the liver is relatively less severe compared to other organ systems, it still experiences an infiltration of innate immune cells and heightened inflammation levels. This review will elaborate on how aging affects the liver's innate immune cells, such as neutrophils, macrophages, dendritic cells, mast cells, and innate lymphoid cells. It will also explore potential strategies for delaying immunosenescence to alleviate these age-related changes.
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Affiliation(s)
- Yan Lin
- Experimental Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
- Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Qiao Li
- Experimental Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
- Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Guangyu Liang
- Experimental Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
- Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Nanyin Xiao
- Experimental Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
- Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Jiankun Yang
- Experimental Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
- Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Xiao Yang
- Experimental Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
- Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Heng Zhang
- Experimental Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
- Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Cuntai Zhang
- Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
- Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Anding Liu
- Experimental Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
- Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
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15
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Tang C, Cen L, Zeng H, Zhang X, Liu P, Chen Y, Song X, Lin B, Zhang X, Yu C, Xu C. Inhibiting Hepatocyte Uric Acid Synthesis and Reabsorption Ameliorates Acetaminophen-Induced Acute Liver Injury in Mice. Cell Mol Gastroenterol Hepatol 2023; 17:251-265. [PMID: 37879407 PMCID: PMC10765060 DOI: 10.1016/j.jcmgh.2023.10.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Revised: 10/17/2023] [Accepted: 10/17/2023] [Indexed: 10/27/2023]
Abstract
BACKGROUND & AIMS Acetaminophen (APAP) overdose is the most common cause of drug-induced liver injury worldwide. Uric acid (UA) is involved in sterile inflammation in many organs, but its role in APAP-induced liver injury remains elusive. METHODS We quantified the concentration of UA in the serum and liver tissues of APAP-overdosed mice and explored the changes in proteins involved in UA synthesis, absorption, and degeneration on APAP stimulation. We also examined the effects of inhibiting hepatocyte UA synthesis or reabsorption on APAP-induced liver injury in mice. Furthermore, we explored the process of UA clearance by peripheral macrophages. RESULTS APAP overdose significantly increased intrahepatic UA contents, which occurred earlier than apparent hepatocyte injury in APAP-overdosed mice. APAP overdose induced significant DNA leakage and may thereby increase the substrate of UA synthesis. APAP overdose also significantly increased the enzymatic activity of xanthine oxidase and urate oxidase and decreased the expression of the UA reabsorption transporter GLUT9 in hepatocytes. Inhibiting hepatocyte UA synthesis by febuxostat or reabsorption by hepatic-specific knockout of GLUT9 alleviated APAP-induced liver injury. Further experiments showed that monosodium urate but not soluble UA may be a major form of UA mediating hepatocyte injury. Additionally, monosodium urate further recruited circulating macrophages into the liver and then aggravated inflammation by increasing the levels of inflammatory factors and reactive oxygen species. Deletion of macrophages significantly ameliorated APAP-induced liver injury in mice. CONCLUSIONS APAP overdose induces excessive UA production and leads to local high concentrations in the liver, which further injures cells and induces liver inflammation. Inhibiting the production of UA may be a potential therapeutic option for treating APAP-induced liver injury.
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Affiliation(s)
- Chenxi Tang
- Department of Gastroenterology, Zhejiang Provincial Clinical Research Center for Digestive Diseases, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Li Cen
- Department of Gastroenterology, Zhejiang Provincial Clinical Research Center for Digestive Diseases, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Hang Zeng
- Department of Gastroenterology, Zhejiang Provincial Clinical Research Center for Digestive Diseases, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xiaofen Zhang
- Department of Gastroenterology, Zhejiang Provincial Clinical Research Center for Digestive Diseases, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Peihao Liu
- Department of Gastroenterology, Zhejiang Provincial Clinical Research Center for Digestive Diseases, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yishu Chen
- Department of Gastroenterology, Zhejiang Provincial Clinical Research Center for Digestive Diseases, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xin Song
- Department of Gastroenterology, Zhejiang Provincial Clinical Research Center for Digestive Diseases, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Bingru Lin
- Department of Gastroenterology, Zhejiang Provincial Clinical Research Center for Digestive Diseases, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xuequn Zhang
- Department of Gastroenterology, Zhejiang Provincial Clinical Research Center for Digestive Diseases, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Chaohui Yu
- Department of Gastroenterology, Zhejiang Provincial Clinical Research Center for Digestive Diseases, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
| | - Chengfu Xu
- Department of Gastroenterology, Zhejiang Provincial Clinical Research Center for Digestive Diseases, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
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16
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Matsuo S, Nabekura T, Matsuda K, Shibuya K, Shibuya A. DNAM-1 Immunoreceptor Protects Mice from Concanavalin A-Induced Acute Liver Injury by Reducing Neutrophil Infiltration. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2023; 211:954-963. [PMID: 37522739 DOI: 10.4049/jimmunol.2200705] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Accepted: 07/13/2023] [Indexed: 08/01/2023]
Abstract
DNAX accessory molecule-1 (DNAM-1; CD226) is an activating immunoreceptor on T cells and NK cells. The interaction of DNAM-1 with its ligand CD155 expressed on hematopoietic and nonhematopoietic cells plays an important role in innate and adaptive immune responses. In this study, we investigated the role of the DNAM-1-CD155 axis in the pathogenesis of T cell-mediated Con A-induced acute liver injury. Unexpectedly, DNAM-1-deficient (Cd226-/-) mice exhibited more severe acute liver injury and higher concentrations of IL-6 and TNF-α than did wild-type (WT) mice after Con A injection. We found that a larger number of neutrophils infiltrated into the liver of Cd226-/- mice compared with WT mice after Con A injection. Depletion of neutrophils ameliorated liver injury and decreased IL-6 and TNF-α in Cd226-/- mice after Con A injection, suggesting that neutrophils exacerbate the liver injury in Cd226-/- mice. Hepatocytes produced more significant amounts of CXCL1, a chemoattractant for neutrophils, in Cd226-/- mice than in WT mice after Con A injection. In the coculture of hepatocytes with liver lymphocytes, either DNAM-1 deficiency in liver lymphocytes or CD155 deficiency in hepatocytes promoted CXCL1 production by hepatocytes. These results suggest that the interaction of DNAM-1 with CD155 inhibits CXCL1 production by hepatocytes, leading to ameliorating acute liver injury.
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Affiliation(s)
- Soichi Matsuo
- Department of Immunology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
- Doctoral Program in Medical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Tsukasa Nabekura
- Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance, University of Tsukuba, Tsukuba, Ibaraki, Japan
- R&D Center for Innovative Drug Discovery, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Kenshiro Matsuda
- Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance, University of Tsukuba, Tsukuba, Ibaraki, Japan
- R&D Center for Innovative Drug Discovery, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Kazuko Shibuya
- Department of Immunology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
- R&D Center for Innovative Drug Discovery, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Akira Shibuya
- Department of Immunology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
- Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance, University of Tsukuba, Tsukuba, Ibaraki, Japan
- R&D Center for Innovative Drug Discovery, University of Tsukuba, Tsukuba, Ibaraki, Japan
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17
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Sun M, Chen P, Xiao K, Zhu X, Zhao Z, Guo C, He X, Shi T, Zhong Q, Jia Y, Tao Y, Li M, Leong KW, Shao D. Circulating Cell-Free DNAs as a Biomarker and Therapeutic Target for Acetaminophen-Induced Liver Injury. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023; 10:e2206789. [PMID: 37035952 PMCID: PMC10238175 DOI: 10.1002/advs.202206789] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/19/2022] [Revised: 01/08/2023] [Indexed: 06/04/2023]
Abstract
Acetaminophen (APAP) overdose is a leading cause of drug-induced liver injury and acute liver failure, while the detection, prognosis prediction, and therapy for APAP-induced liver injury (AILI) remain improved. Here, it is determined that the temporal pattern of circulating cell-free DNA (cfDNA) is strongly associated with damage and inflammation parameters in AILI. CfDNA is comparable to alanine aminotransferase (ALT) in predicting mortality and outperformed ALT when combined with ALT in AILI. The depletion of cfDNA or neutrophils alleviates liver damage, while the addition of cfDNA or adoptive transfer of neutrophils exacerbates the damage. The combination of DNase I and N-acetylcysteine attenuates AILI significantly. This study establishes that cfDNA is a mechanistic biomarker to predict mortality in AILI mice. The combination of scavenging cfDNA and reducing oxidative damage provides a promising treatment for AILI.
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Affiliation(s)
- Madi Sun
- School of Biomedical Sciences and EngineeringSouth China University of TechnologyGuangzhou International CampusGuangzhouGuangdong510630China
- National Engineering Research Center for Tissue Restoration and ReconstructionSouth China University of TechnologyGuangzhou International CampusGuangzhouGuangdong510630China
| | - Peiyu Chen
- School of Biomedical Sciences and EngineeringSouth China University of TechnologyGuangzhou International CampusGuangzhouGuangdong510630China
- National Engineering Research Center for Tissue Restoration and ReconstructionSouth China University of TechnologyGuangzhou International CampusGuangzhouGuangdong510630China
| | - Kai Xiao
- National Engineering Research Center for Tissue Restoration and ReconstructionSouth China University of TechnologyGuangzhou International CampusGuangzhouGuangdong510630China
- School of MedicineSouth China University of TechnologyGuangzhou International CampusGuangzhouGuangdong510006China
| | - Xiang Zhu
- Laboratory of Biomaterials and Translational MedicineThe Third Affiliated HospitalSun Yat‐sen UniversityGuangzhouGuangdong510006China
| | - Zhibin Zhao
- School of MedicineSouth China University of TechnologyGuangzhou International CampusGuangzhouGuangdong510006China
| | - Chenyang Guo
- School of Biomedical Sciences and EngineeringSouth China University of TechnologyGuangzhou International CampusGuangzhouGuangdong510630China
- National Engineering Research Center for Tissue Restoration and ReconstructionSouth China University of TechnologyGuangzhou International CampusGuangzhouGuangdong510630China
| | - Xuan He
- School of Biomedical Sciences and EngineeringSouth China University of TechnologyGuangzhou International CampusGuangzhouGuangdong510630China
- National Engineering Research Center for Tissue Restoration and ReconstructionSouth China University of TechnologyGuangzhou International CampusGuangzhouGuangdong510630China
| | - Tongfei Shi
- School of Biomedical Sciences and EngineeringSouth China University of TechnologyGuangzhou International CampusGuangzhouGuangdong510630China
- National Engineering Research Center for Tissue Restoration and ReconstructionSouth China University of TechnologyGuangzhou International CampusGuangzhouGuangdong510630China
| | - Qingguo Zhong
- Laboratory of Biomaterials and Translational MedicineThe Third Affiliated HospitalSun Yat‐sen UniversityGuangzhouGuangdong510006China
| | - Yong Jia
- School of NursingJilin UniversityChangchunJilin130021China
| | - Yu Tao
- Laboratory of Biomaterials and Translational MedicineThe Third Affiliated HospitalSun Yat‐sen UniversityGuangzhouGuangdong510006China
| | - Mingqiang Li
- Laboratory of Biomaterials and Translational MedicineThe Third Affiliated HospitalSun Yat‐sen UniversityGuangzhouGuangdong510006China
| | - Kam W. Leong
- Department of Systems BiologyColumbia UniversityNew YorkNY10032USA
| | - Dan Shao
- School of Biomedical Sciences and EngineeringSouth China University of TechnologyGuangzhou International CampusGuangzhouGuangdong510630China
- National Engineering Research Center for Tissue Restoration and ReconstructionSouth China University of TechnologyGuangzhou International CampusGuangzhouGuangdong510630China
- Guangdong Provincial Key Laboratory of Biomedical EngineeringKey Laboratory of Biomedical Materials and Engineering of the Ministry of EducationSouth China University of TechnologyGuangzhouGuangdong510006China
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Zheng J, Yang N, Wan Y, Cheng W, Zhang G, Yu S, Yang B, Liu X, Chen X, Ding X, Wu L, Yu X. Celastrol-loaded biomimetic nanodrug ameliorates APAP-induced liver injury through modulating macrophage polarization. J Mol Med (Berl) 2023:10.1007/s00109-023-02321-8. [PMID: 37129620 DOI: 10.1007/s00109-023-02321-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Revised: 04/11/2023] [Accepted: 04/12/2023] [Indexed: 05/03/2023]
Abstract
Drug-induced liver injury (DILI) is a major concern in clinical treatment as well as postmarketing surveillance, showing an urgent requirement for the development of protective medications. Celastrol (Cel), a highly active natural product extracted from the roots of Tripterygium wilfordii, has a potential liver protective activity due to its antioxidant and anti-inflammatory effects. However, the further application of Cel to DILI remains a challenge because of its short half-life, low solubility, and toxic side effects. Herein, we developed a Cel-loaded biomimetic nanodrug based on erythrocyte membrane vesicles (EMV) for protecting the liver from acetaminophen (APAP)-induced liver injury. The Cel-loaded EMV (C-EMV) with lower cytotoxicity had a well-sustained release effect and exhibited excellent ability for liver accumulation under physiological and pathological conditions. By suppressing the inflammatory response of pro-inflammatory macrophage M1 polarization while stimulating anti-inflammatory macrophage M2 polarization, C-EMV could significantly alleviate the primary pathological manifestations related to liver injury, including aberrant elevation of biochemical indicators, histopathological alterations, neutrophil infiltration as well as hepatocyte DNA fragmentation. The macrophage depletion experiment further demonstrated that the protective effect of C-EMV on APAP-induced liver injury appeared to be dependent on hepatic macrophages. Therefore, C-EMV as a biomimetic nanodrug exhibits great potential for attenuating the progress of DILI, providing a new approach to protecting the liver from DILI as well as other liver inflammatory diseases through a targeted nanodelivery system. KEY MESSAGES: EMV biomimetic nanocarrier has good monodispersity and sustained-release property. EMV biomimetic nanocarrier displays excellent liver-targeting capability under physiological and pathological conditions. C-EMV biomimetic nanodrug with lower cytotoxicity regulates macrophage polarization in vitro and in vivo. C-EMV biomimetic nanodrug can significantly alleviate APAP-induced liver injury. The protective effect of C-EMV on APAP-induced liver injury is dependent on hepatic macrophages.
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Affiliation(s)
- Jing Zheng
- Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, China Three Gorges University, Yichang, China
- Institute of Infection and Inflammation, China Three Gorges University, Yichang, China
- Medical College, China Three Gorges University, Yichang, China
- The People's Hospital of China Three Gorges University, Yichang, China
| | - Ni Yang
- Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, China Three Gorges University, Yichang, China
- Institute of Infection and Inflammation, China Three Gorges University, Yichang, China
- Medical College, China Three Gorges University, Yichang, China
| | - Yingying Wan
- Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, China Three Gorges University, Yichang, China
- Institute of Infection and Inflammation, China Three Gorges University, Yichang, China
- Medical College, China Three Gorges University, Yichang, China
| | - Wenjing Cheng
- Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, China Three Gorges University, Yichang, China
- Institute of Infection and Inflammation, China Three Gorges University, Yichang, China
- Medical College, China Three Gorges University, Yichang, China
| | - Gan Zhang
- Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, China Three Gorges University, Yichang, China
- Institute of Infection and Inflammation, China Three Gorges University, Yichang, China
- Medical College, China Three Gorges University, Yichang, China
| | - Shi Yu
- Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, China Three Gorges University, Yichang, China
- Institute of Infection and Inflammation, China Three Gorges University, Yichang, China
- Medical College, China Three Gorges University, Yichang, China
| | - Baoye Yang
- Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, China Three Gorges University, Yichang, China
- Institute of Infection and Inflammation, China Three Gorges University, Yichang, China
- Medical College, China Three Gorges University, Yichang, China
| | - Xinyu Liu
- Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, China Three Gorges University, Yichang, China
- Institute of Infection and Inflammation, China Three Gorges University, Yichang, China
- Medical College, China Three Gorges University, Yichang, China
| | - Xingyan Chen
- Tong Ji Hospital, Tongji Medical College of HUST, Wuhan, China
| | - Xueliang Ding
- Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, China Three Gorges University, Yichang, China
- Medical College, China Three Gorges University, Yichang, China
- Department of Clinical Laboratory, Affiliated Renhe Hospital of China Three Gorges University, Yichang, China
| | - Ling Wu
- The People's Hospital of China Three Gorges University, Yichang, China.
| | - Xiang Yu
- Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, China Three Gorges University, Yichang, China.
- Institute of Infection and Inflammation, China Three Gorges University, Yichang, China.
- Medical College, China Three Gorges University, Yichang, China.
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Nguyen NT, Umbaugh DS, Smith S, Adelusi OB, Sanchez-Guerrero G, Ramachandran A, Jaeschke H. Dose-dependent pleiotropic role of neutrophils during acetaminophen-induced liver injury in male and female mice. Arch Toxicol 2023; 97:1397-1412. [PMID: 36928416 PMCID: PMC10680445 DOI: 10.1007/s00204-023-03478-4] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Accepted: 03/02/2023] [Indexed: 03/18/2023]
Abstract
Acetaminophen (APAP) overdose is the leading cause of acute liver failure in western countries. APAP can cause extensive hepatocellular necrosis, which triggers an inflammatory response involving neutrophil and monocyte recruitment. Particularly the role of neutrophils in the injury mechanism of APAP hepatotoxicity has been highly controversial. Thus, the objective of the current study was to assess whether a potential contribution of neutrophils was dependent on the APAP dose and the sex of the animals. Male and female C57BL/6 J mice were treated with 300 or 600 mg/kg APAP and the injury and inflammatory cell recruitment was evaluated between 6 and 48 h. In both male and female mice, ALT plasma levels and the areas of necrosis peaked at 12-24 h after both doses with more severe injury at the higher dose. In addition, Ly6g-positive neutrophils started to accumulate in the liver at 6 h and peaked at 6-12 h after 300 mg/kg and 12-24 h after 600 mg/kg for both sexes; however, the absolute numbers of hepatic neutrophils in the liver were significantly higher after the 600 mg/kg dose. Neutrophil infiltration correlated with mRNA levels of the neutrophil chemoattractant Cxcl2 in the liver. Treating mice with an anti-Cxcl2 antibody at 2 h after APAP significantly reduced neutrophil accumulation at 24 h after both doses and in both sexes. However, the injury was significantly reduced only after the high overdose. Thus, neutrophils, recruited through Cxcl2, have no effect on APAP-induced liver injury after 300 mg/kg but aggravate the injury only after severe overdoses.
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Affiliation(s)
- Nga T Nguyen
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd, MS 1018, Kansas City, Kansas, 66160, USA
| | - David S Umbaugh
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd, MS 1018, Kansas City, Kansas, 66160, USA
| | - Sawyer Smith
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd, MS 1018, Kansas City, Kansas, 66160, USA
| | - Olamide B Adelusi
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd, MS 1018, Kansas City, Kansas, 66160, USA
| | - Giselle Sanchez-Guerrero
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd, MS 1018, Kansas City, Kansas, 66160, USA
| | - Anup Ramachandran
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd, MS 1018, Kansas City, Kansas, 66160, USA
| | - Hartmut Jaeschke
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd, MS 1018, Kansas City, Kansas, 66160, USA.
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20
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Ishida Y, Zhang S, Kuninaka Y, Ishigami A, Nosaka M, Harie I, Kimura A, Mukaida N, Kondo T. Essential Involvement of Neutrophil Elastase in Acute Acetaminophen Hepatotoxicity Using BALB/c Mice. Int J Mol Sci 2023; 24:7845. [PMID: 37175553 PMCID: PMC10177873 DOI: 10.3390/ijms24097845] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Revised: 04/22/2023] [Accepted: 04/24/2023] [Indexed: 05/15/2023] Open
Abstract
Intense neutrophil infiltration into the liver is a characteristic of acetaminophen-induced acute liver injury. Neutrophil elastase is released by neutrophils during inflammation. To elucidate the involvement of neutrophil elastase in acetaminophen-induced liver injury, we investigated the efficacy of a potent and specific neutrophil elastase inhibitor, sivelestat, in mice with acetaminophen-induced acute liver injury. Intraperitoneal administration of 750 mg/kg of acetaminophen caused severe liver damage, such as elevated serum transaminase levels, centrilobular hepatic necrosis, and neutrophil infiltration, with approximately 50% mortality in BALB/c mice within 48 h of administration. However, in mice treated with sivelestat 30 min after the acetaminophen challenge, all mice survived, with reduced serum transaminase elevation and diminished hepatic necrosis. In addition, mice treated with sivelestat had reduced NOS-II expression and hepatic neutrophil infiltration after the acetaminophen challenge. Furthermore, treatment with sivelestat at 3 h after the acetaminophen challenge significantly improved survival. These findings indicate a new clinical application for sivelestat in the treatment of acetaminophen-induced liver failure through mechanisms involving the regulation of neutrophil migration and NO production.
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Affiliation(s)
- Yuko Ishida
- Department of Forensic Medicine, Wakayama Medical University, Wakayama 641-0012, Japan
| | | | | | | | | | | | | | | | - Toshikazu Kondo
- Department of Forensic Medicine, Wakayama Medical University, Wakayama 641-0012, Japan
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21
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Wang Z, Sun P, Pan B, Qiu J, Zhang X, Shen S, Ke X, Tang N. IL-33/ST2 antagonizes STING signal transduction via autophagy in response to acetaminophen-mediated toxicological immunity. Cell Commun Signal 2023; 21:80. [PMID: 37081450 PMCID: PMC10116723 DOI: 10.1186/s12964-023-01114-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Accepted: 03/25/2023] [Indexed: 04/22/2023] Open
Abstract
BACKGROUND Interleukin-33 (IL-33), defined as "alarming", exert diverse functions through signaling via the suppression of tumorigenicity 2 (ST2). However, the physiological roles of IL-33/ST2 signaling during acetaminophen (APAP)-induced liver injury are still poorly understood by modern medicine (AILI). This research aims to explore the relationship between IL-33/ST2 and stimulator of interferon (IFN) response cGAMP interactor 1 (STING)-mediated signal transduction. METHODS C57BL/6N mice (WT) and IL-33-deficient mice (KO) were intraperitoneally injected with APAP (250 mg/kg). Recombinant IL-33 (500 ng/mouse) and the cGAS/STING inhibitor RU.521 (200 g/kg) were combined to treat AILI. For mechanistic research in vitro, CRISPR-mediated KD technology, immunoprecipitation, mass spectrometry, and immunofluorescence were utilized. RESULTS We discovered that IL-33 deficient mice had increased APAP-induced hepatotoxicity, DNA accumulation, and type 1 IFN production. Mechanistic analysis revealed that IL-33/ST2 enhanced the interaction between Beclin-1 and STING, disrupting STING dimerization, IRF3 phosphorylation, nuclear transport, and IFN-1 gene transcription in HepaRG and Huh7 cells. Beclin-1 interacted with the C-terminus of STING, causing Lys338 acetylation and autophagy degradation of STING. ST2 depletion increased STING signal transduction and IFN-1 promoter activity. Surprisingly, the cGAS/STING inhibitor RU.521 and recombinant IL-33 together improved AILI in vivo. CONCLUSIONS These results shed insight on the potential of inhibiting cGAS/STING as a therapy for AILI and emphasize the crucial role of IL-33/ST2 signaling in the regulation of APAP-induced STING signaling. Video Abstract.
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Affiliation(s)
- Zengbin Wang
- Department of Hepatobiliary Surgery and Fujian Institute of Hepatobiliary Surgery, Cancer Center of Fujian Medical University, Fujian Medical University Union Hospital, Fuzhou, China
| | - Pei Sun
- College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, China
| | - Banglun Pan
- Department of Hepatobiliary Surgery and Fujian Institute of Hepatobiliary Surgery, Cancer Center of Fujian Medical University, Fujian Medical University Union Hospital, Fuzhou, China
| | - Jiacheng Qiu
- Department of Hepatobiliary Surgery and Fujian Institute of Hepatobiliary Surgery, Cancer Center of Fujian Medical University, Fujian Medical University Union Hospital, Fuzhou, China
| | - Xiaoxia Zhang
- Department of Hepatobiliary Surgery and Fujian Institute of Hepatobiliary Surgery, Cancer Center of Fujian Medical University, Fujian Medical University Union Hospital, Fuzhou, China
| | - Shuling Shen
- Department of Hepatobiliary Surgery and Fujian Institute of Hepatobiliary Surgery, Cancer Center of Fujian Medical University, Fujian Medical University Union Hospital, Fuzhou, China
| | - Xiaoling Ke
- Department of Hepatobiliary Surgery and Fujian Institute of Hepatobiliary Surgery, Cancer Center of Fujian Medical University, Fujian Medical University Union Hospital, Fuzhou, China
| | - Nanhong Tang
- Department of Hepatobiliary Surgery and Fujian Institute of Hepatobiliary Surgery, Cancer Center of Fujian Medical University, Fujian Medical University Union Hospital, Fuzhou, China.
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Research Center for Molecular Medicine, Fujian Medical University, Fuzhou, China.
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22
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Amorim R, Magalhães CC, Borges F, Oliveira PJ, Teixeira J. From Non-Alcoholic Fatty Liver to Hepatocellular Carcinoma: A Story of (Mal)Adapted Mitochondria. BIOLOGY 2023; 12:biology12040595. [PMID: 37106795 PMCID: PMC10135755 DOI: 10.3390/biology12040595] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Revised: 03/30/2023] [Accepted: 04/11/2023] [Indexed: 04/29/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a global pandemic affecting 25% of the world's population and is a serious health and economic concern worldwide. NAFLD is mainly the result of unhealthy dietary habits combined with sedentary lifestyle, although some genetic contributions to NAFLD have been documented. NAFLD is characterized by the excessive accumulation of triglycerides (TGs) in hepatocytes and encompasses a spectrum of chronic liver abnormalities, ranging from simple steatosis (NAFL) to steatohepatitis (NASH), significant liver fibrosis, cirrhosis, and hepatocellular carcinoma. Although the molecular mechanisms that cause the progression of steatosis to severe liver damage are not fully understood, metabolic-dysfunction-associated fatty liver disease is strong evidence that mitochondrial dysfunction plays a significant role in the development and progression of NAFLD. Mitochondria are highly dynamic organelles that undergo functional and structural adaptations to meet the metabolic requirements of the cell. Alterations in nutrient availability or cellular energy needs can modify mitochondria formation through biogenesis or the opposite processes of fission and fusion and fragmentation. In NAFL, simple steatosis can be seen as an adaptive response to storing lipotoxic free fatty acids (FFAs) as inert TGs due to chronic perturbation in lipid metabolism and lipotoxic insults. However, when liver hepatocytes' adaptive mechanisms are overburdened, lipotoxicity occurs, contributing to reactive oxygen species (ROS) formation, mitochondrial dysfunction, and endoplasmic reticulum (ER) stress. Impaired mitochondrial fatty acid oxidation, reduction in mitochondrial quality, and disrupted mitochondrial function are associated with a decrease in the energy levels and impaired redox balance and negatively affect mitochondria hepatocyte tolerance towards damaging hits. However, the sequence of events underlying mitochondrial failure from steatosis to hepatocarcinoma is still yet to be fully clarified. This review provides an overview of our understanding of mitochondrial adaptation in initial NAFLD stages and highlights how hepatic mitochondrial dysfunction and heterogeneity contribute to disease pathophysiology progression, from steatosis to hepatocellular carcinoma. Improving our understanding of different aspects of hepatocytes' mitochondrial physiology in the context of disease development and progression is crucial to improving diagnosis, management, and therapy of NAFLD/NASH.
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Affiliation(s)
- Ricardo Amorim
- CNC-Center for Neuroscience and Cell Biology, CIBB-Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, 3004-504 Coimbra, Portugal
- CIQUP-IMS/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, 4169-007 Porto, Portugal
| | - Carina C Magalhães
- CNC-Center for Neuroscience and Cell Biology, CIBB-Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, 3004-504 Coimbra, Portugal
| | - Fernanda Borges
- CIQUP-IMS/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, 4169-007 Porto, Portugal
| | - Paulo J Oliveira
- CNC-Center for Neuroscience and Cell Biology, CIBB-Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, 3004-504 Coimbra, Portugal
| | - José Teixeira
- CNC-Center for Neuroscience and Cell Biology, CIBB-Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, 3004-504 Coimbra, Portugal
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23
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Moustafa AH, Pasha HF, Abas MA, Aboregela AM. The ameliorating role of sofosbuvir and daclatasvir on thioacetamide-induced kidney injury in adult albino rats. Anat Cell Biol 2023; 56:109-121. [PMID: 36543744 PMCID: PMC9989782 DOI: 10.5115/acb.22.200] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Revised: 11/06/2022] [Accepted: 11/21/2022] [Indexed: 12/24/2022] Open
Abstract
Thioacetamide (TAA) exposure and hepatitis C virus infection are usually associated with renal dysfunction. Sofosbuvir (SFV) and daclatasvir (DAC) drugs combination has great value in the treatment of hepatitis C. The study aimed to identify the nephrotoxic effects of TAA and to evaluate the ameliorative role of SFV and DAC in this condition. Forty-eight adult male albino rats were divided into eight groups and received saline (control), SFV, DAC, SFV+DAC, TAA, TAA+SFV, TAA+DAC and TAA+SFV+DAC for eight weeks. Kidney and blood samples were retrieved and processed for histological (Hematoxylin and Eosin and Masson's trichrome), immunohistochemical (α-smooth muscle actin), and biochemical analysis (urea, creatinine, total protein, albumin, malondialdehyde, reduced glutathione, superoxide dismutase, and tumor necrosis factor-α). Examination revealed marked destruction of renal tubules on exposure to TAA with either hypertrophy or atrophy of glomeruli, increase in collagen deposition, and wide expression of α-smooth muscle actin. Also, significant disturbance in kidney functions, oxidative stress markers, and tumor necrosis factor-α. Supplementation with either SFV or DAC produced mild improvement in the tissue and laboratory markers. Moreover, the combination of both drugs greatly refined the pathology induced by TAA at the cellular and laboratory levels. However, there are still significant differences when compared to the control. In conclusion, SFV and DAC combination partially but greatly ameliorated the renal damage induced by TAA which might be enhanced with further supplementations to give new hope for those with nephropathy associated with hepatitis.
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Affiliation(s)
- Ahmed H Moustafa
- Department of Chemistry, Faculty of Science, Zagazig University, Zagazig, Egypt
| | - Heba F Pasha
- Department of Medical Biochemistry and Genetics, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Manar A Abas
- Department of Biochemistry, Faculty of Science, Zagazig University, Zagazig, Egypt
| | - Adel M Aboregela
- Department of Human Anatomy and Embryology, Faculty of Medicine, Zagazig University, Zagazig, Egypt.,Department of Basic Medical Sciences, College of Medicine, University of Bisha, Bisha, Saudi Arabia
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24
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Xu L, Wang H. A dual role of inflammation in acetaminophen-induced liver injury. LIVER RESEARCH 2023; 7:9-15. [PMID: 39959696 PMCID: PMC11791818 DOI: 10.1016/j.livres.2023.03.001] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Revised: 01/14/2023] [Accepted: 03/05/2023] [Indexed: 03/12/2023]
Abstract
In many affluent nations, acetaminophen (APAP) overdose is the leading cause of drug-induced acute liver failure. The process of APAP-induced liver injury (AILI) is intimately tied to inflammation, including hepatocyte necrosis-caused initiation of inflammation, inflammation amplification that exacerbates liver injury, and the resolution of inflammation that triggers liver regeneration and repair. Excessive APAP metabolism in the liver eventually leads to hepatocyte necrosis and inflammation. Innate immune cells, such as neutrophils, eosinophils, monocytes, and gammadelta T cells, are recruited into the injured liver and release various cytokines. These immune cells and cytokines have been found to serve two purposes in AILI. In this review, we highlighted the dual role of inflammation, including inflammatory cytokines and inflammatory immune cells in AILI, and discussed possible explanations for contradictory findings.
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Affiliation(s)
- Long Xu
- School of Basic Medical Science, Anhui Medical University, Hefei, Anhui, China
| | - Hua Wang
- Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
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25
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Hildreth AD, Padilla ET, Tafti RY, Legala AR, O'Sullivan TE. Sterile liver injury induces a protective tissue-resident cDC1-ILC1 circuit through cDC1-intrinsic cGAS-STING-dependent IL-12 production. Cell Rep 2023; 42:112141. [PMID: 36807146 PMCID: PMC10435668 DOI: 10.1016/j.celrep.2023.112141] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Revised: 11/02/2022] [Accepted: 02/06/2023] [Indexed: 02/22/2023] Open
Abstract
Tissue-resident immune cells are critical to the initiation and potentiation of inflammation. However, the tissue-protective cellular communication networks initiated by resident immunity during sterile inflammation are not well understood. Using single-cell transcriptomic analysis, we show the liver-resident cell connectome and signalome during acute liver injury. These analyses identify Il12b as a central regulator of liver injury-associated changes in gene expression. Interleukin (IL)-12 produced by conventional type 1 dendritic cells (cDC1s) is required for protection during acute injury through activation of interferon (IFN)-γ production by liver-resident type 1 innate lymphoid cells (ILC1s). Using a targeted in vivo CRISPR-Cas9 screen of innate immune sensing pathways, we find that cDC1-intrinsic cGAS-STING signaling acts upstream of IL-12 production to initiate early protective immune responses. Our study identifies the core communication hubs initiated by tissue-resident innate immune cells during sterile inflammation in vivo and implicates cDC1-derived IL-12 as an important regulator of this process.
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Affiliation(s)
- Andrew D Hildreth
- Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Eddie T Padilla
- Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
| | - Rana Yakhshi Tafti
- Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
| | - Akshara R Legala
- Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
| | - Timothy E O'Sullivan
- Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.
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26
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Janovičová Ľ, Kmeťová K, Pribulová N, Janko J, Gromová B, Gardlík R, Celec P. Endogenous DNase Activity in an Animal Model of Acute Liver Failure. Int J Mol Sci 2023; 24:ijms24032984. [PMID: 36769306 PMCID: PMC9918174 DOI: 10.3390/ijms24032984] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Revised: 01/23/2023] [Accepted: 01/30/2023] [Indexed: 02/05/2023] Open
Abstract
Deoxyribonucleases (DNases) cleave extracellular DNA (ecDNA) and are under intense research as interventions for diseases associated with high ecDNA, such as acute live injury. DNase I treatment decreases morbidity and mortality in this animal model. Endogenous DNase activity has high interindividual variability. In this study, we tested the hypothesis that high endogenous DNase activity is beneficial in an animal model of acute liver failure. DNase activity was measured in the plasma of adult male mice taken before i.p. injection of thioacetamide to induce acute liver failure. The survival of mice was monitored for 48 h. Mice were retrospectively divided into two groups based on the median DNase activity assessed using the gel-based single-radial enzyme diffusion assay. In acute liver failure, mice with a higher baseline DNase activity had lower mortality after 48 h (by 25%). Different protection of ecDNA against nucleases by vesicles or DNA-binding proteins could play a role and should be further evaluated. Similarly, the role of endogenous DNase activity should be analyzed in other disease models associated with high ecDNA.
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Affiliation(s)
- Ľubica Janovičová
- Institute of Molecular Biomedicine, Faculty of Medicine, Comenius University, 81108 Bratislava, Slovakia
| | - Katarína Kmeťová
- Institute of Molecular Biomedicine, Faculty of Medicine, Comenius University, 81108 Bratislava, Slovakia
| | - Nikola Pribulová
- Institute of Molecular Biomedicine, Faculty of Medicine, Comenius University, 81108 Bratislava, Slovakia
| | - Jakub Janko
- Institute of Molecular Biomedicine, Faculty of Medicine, Comenius University, 81108 Bratislava, Slovakia
| | - Barbora Gromová
- Institute of Molecular Biomedicine, Faculty of Medicine, Comenius University, 81108 Bratislava, Slovakia
| | - Roman Gardlík
- Institute of Molecular Biomedicine, Faculty of Medicine, Comenius University, 81108 Bratislava, Slovakia
- Institute of Pathophysiology, Faculty of Medicine, Comenius University, 81108 Bratislava, Slovakia
| | - Peter Celec
- Institute of Molecular Biomedicine, Faculty of Medicine, Comenius University, 81108 Bratislava, Slovakia
- Institute of Pathophysiology, Faculty of Medicine, Comenius University, 81108 Bratislava, Slovakia
- Correspondence: or
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27
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Abstract
Acetaminophen (APAP) is a widely used pain reliever that can cause liver injury or liver failure in response to an overdose. Understanding the mechanisms of APAP-induced cell death is critical for identifying new therapeutic targets. In this respect it was hypothesized that hepatocytes die by oncotic necrosis, apoptosis, necroptosis, ferroptosis and more recently pyroptosis. The latter cell death is characterized by caspase-dependent gasdermin cleavage into a C-terminal and an N-terminal fragment, which forms pores in the plasma membrane. The gasdermin pores can release potassium, interleukin-1β (IL-1β), IL-18, and other small molecules in a sublytic phase, which can be the main function of the pores in certain cell types such as inflammatory cells. Alternatively, the process can progress to full lysis of the cell (pyroptosis) with extensive cell contents release. This review discusses the experimental evidence for the involvement of pyroptosis in APAP hepatotoxicity as well as the arguments against pyroptosis as a relevant mechanism of APAP-induced cell death in hepatocytes. Based on the critical evaluation of the currently available literature and understanding of the pathophysiology, it can be concluded that pyroptotic cell death is unlikely to be a relevant contributor to APAP-induced liver injury.
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Affiliation(s)
- Hartmut Jaeschke
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - David S. Umbaugh
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Anup Ramachandran
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
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Li Q, Chen F, Wang F. The immunological mechanisms and therapeutic potential in drug-induced liver injury: lessons learned from acetaminophen hepatotoxicity. Cell Biosci 2022; 12:187. [PMID: 36414987 PMCID: PMC9682794 DOI: 10.1186/s13578-022-00921-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Accepted: 11/01/2022] [Indexed: 11/24/2022] Open
Abstract
Acute liver failure caused by drug overdose is a significant clinical problem in developed countries. Acetaminophen (APAP), a widely used analgesic and antipyretic drug, but its overdose can cause acute liver failure. In addition to APAP-induced direct hepatotoxicity, the intracellular signaling mechanisms of APAP-induced liver injury (AILI) including metabolic activation, mitochondrial oxidant stress and proinflammatory response further affect progression and severity of AILI. Liver inflammation is a result of multiple interactions of cell death molecules, immune cell-derived cytokines and chemokines, as well as damaged cell-released signals which orchestrate hepatic immune cell infiltration. The immunoregulatory interplay of these inflammatory mediators and switching of immune responses during AILI lead to different fate of liver pathology. Thus, better understanding the complex interplay of immune cell subsets in experimental models and defining their functional involvement in disease progression are essential to identify novel therapeutic targets for the treatment of AILI. Here, this present review aims to systematically elaborate on the underlying immunological mechanisms of AILI, its relevance to immune cells and their effector molecules, and briefly discuss great therapeutic potential based on inflammatory mediators.
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Affiliation(s)
- Qianhui Li
- grid.511083.e0000 0004 7671 2506Division of Gastroenterology, Seventh Affiliated Hospital of Sun Yat-sen University, No.628, Zhenyuan Road, Shenzhen, 518107 China
| | - Feng Chen
- grid.511083.e0000 0004 7671 2506Division of Gastroenterology, Seventh Affiliated Hospital of Sun Yat-sen University, No.628, Zhenyuan Road, Shenzhen, 518107 China
| | - Fei Wang
- grid.511083.e0000 0004 7671 2506Division of Gastroenterology, Seventh Affiliated Hospital of Sun Yat-sen University, No.628, Zhenyuan Road, Shenzhen, 518107 China
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29
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Hirako IC, Antunes MM, Rezende RM, Hojo-Souza NS, Figueiredo MM, Dias T, Nakaya H, Menezes GB, Gazzinelli RT. Uptake of Plasmodium chabaudi hemozoin drives Kupffer cell death and fuels superinfections. Sci Rep 2022; 12:19805. [PMID: 36396745 PMCID: PMC9671901 DOI: 10.1038/s41598-022-23858-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Accepted: 11/07/2022] [Indexed: 11/18/2022] Open
Abstract
Kupffer cells (KCs) are self-maintained tissue-resident macrophages that line liver sinusoids and play an important role on host defense. It has been demonstrated that upon infection or intense liver inflammation, KCs might be severely depleted and replaced by immature monocytic cells; however, the mechanisms of cell death and the alterations on liver immunity against infections deserves further investigation. We explored the impact of acute Plasmodium infection on KC biology and on the hepatic immune response against secondary infections. Similar to patients, infection with Plasmodium chabaudi induced acute liver damage as determined by serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) elevation. This was associated with accumulation of hemozoin, increased of proinflammatory response and impaired bacterial and viral clearance, which led to pathogen spread to other organs. In line with this, mice infected with Plasmodium had enhanced mortality during secondary infections, which was associated with increased production of mitochondrial superoxide, lipid peroxidation and increased free iron within KCs-hallmarks of cell death by ferroptosis. Therefore, we revealed that accumulation of iron with KCs, triggered by uptake of circulating hemozoin, is a novel mechanism of macrophage depletion and liver inflammation during malaria, providing novel insights on host susceptibility to secondary infections. Malaria can cause severe liver damage, along with depletion of liver macrophages, which can predispose individuals to secondary infections and enhance the chances of death.
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Affiliation(s)
- Isabella C Hirako
- Instituto René Rachou, Fundação Oswaldo Cruz, Belo Horizonte, MG, Brazil
- Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, 364 Plantation Street, Lazare Research Building, 3rd Floor, Worcester, MA, USA
| | - Maísa Mota Antunes
- Center for Gastrointestinal Biology, Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - Rafael Machado Rezende
- Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | | | | | - Thomaz Dias
- Escola de Ciências Farmacêuticas - Universidade de São Paulo, São Paulo, SP, Brazil
| | - Helder Nakaya
- Escola de Ciências Farmacêuticas - Universidade de São Paulo, São Paulo, SP, Brazil
| | - Gustavo Batista Menezes
- Center for Gastrointestinal Biology, Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - Ricardo Tostes Gazzinelli
- Instituto René Rachou, Fundação Oswaldo Cruz, Belo Horizonte, MG, Brazil.
- Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, 364 Plantation Street, Lazare Research Building, 3rd Floor, Worcester, MA, USA.
- Departamento de Bioquímica E Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil.
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30
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Amaral EP, Foreman TW, Namasivayam S, Hilligan KL, Kauffman KD, Barbosa Bomfim CC, Costa DL, Barreto-Duarte B, Gurgel-Rocha C, Santana MF, Cordeiro-Santos M, Du Bruyn E, Riou C, Aberman K, Wilkinson RJ, Barber DL, Mayer-Barber KD, Andrade BB, Sher A. GPX4 regulates cellular necrosis and host resistance in Mycobacterium tuberculosis infection. J Exp Med 2022; 219:e20220504. [PMID: 36069923 PMCID: PMC9458471 DOI: 10.1084/jem.20220504] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Revised: 06/23/2022] [Accepted: 08/11/2022] [Indexed: 01/15/2023] Open
Abstract
Cellular necrosis during Mycobacterium tuberculosis (Mtb) infection promotes both immunopathology and bacterial dissemination. Glutathione peroxidase-4 (Gpx4) is an enzyme that plays a critical role in preventing iron-dependent lipid peroxidation-mediated cell death (ferroptosis), a process previously implicated in the necrotic pathology seen in Mtb-infected mice. Here, we document altered GPX4 expression, glutathione levels, and lipid peroxidation in patients with active tuberculosis and assess the role of this pathway in mice genetically deficient in or overexpressing Gpx4. We found that Gpx4-deficient mice infected with Mtb display substantially increased lung necrosis and bacterial burdens, while transgenic mice overexpressing the enzyme show decreased bacterial loads and necrosis. Moreover, Gpx4-deficient macrophages exhibited enhanced necrosis upon Mtb infection in vitro, an outcome suppressed by the lipid peroxidation inhibitor, ferrostatin-1. These findings provide support for the role of ferroptosis in Mtb-induced necrosis and implicate the Gpx4/GSH axis as a target for host-directed therapy of tuberculosis.
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Affiliation(s)
- Eduardo P. Amaral
- Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD
| | - Taylor W. Foreman
- T Lymphocyte Biology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD
| | - Sivaranjani Namasivayam
- Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD
| | - Kerry L. Hilligan
- Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD
| | - Keith D. Kauffman
- T Lymphocyte Biology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD
| | - Caio Cesar Barbosa Bomfim
- Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD
| | - Diego L. Costa
- Departmento de Bioquímica e Imunologia, Programa de Pós-Graduação em Imunologia Básica e Aplicada, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil
| | - Beatriz Barreto-Duarte
- Laboratório de Inflamação e Biomarcadores, Instituto Gonçalo Moniz, Fundação Oswaldo Cruz, Salvador, Bahia, Brazil
- Multinational Organization Network Sponsoring Translational and Epidemiological Research Initiative, Salvador, Brazil
- Curso de Medicina, Universidade Salvador, Laureate Universities, Salvador, Brazil
| | - Clarissa Gurgel-Rocha
- Department of Pathology, School of Medicine of the Federal University of Bahia, Salvador, Bahia, Brazil
- Center for Biotechnology and Cell Therapy, D’Or Institute for Research and Education, Sao Rafael Hospital, Salvador, Bahia, Brazil
| | - Monique Freire Santana
- Departmento de Ensino e Pesquisa, Fundação Centro de Controle de Oncologia do Estado do Amazonas, Manaus, Brazil
- Fundação Medicina Tropical Doutor Heitor Vieira Dourado, Manaus, Brazil
- Programa de Pós-Graduação em Medicina Tropical, Universidade do Estado do Amazonas, Manaus, Brazil
| | - Marcelo Cordeiro-Santos
- Fundação Medicina Tropical Doutor Heitor Vieira Dourado, Manaus, Brazil
- Programa de Pós-Graduação em Medicina Tropical, Universidade do Estado do Amazonas, Manaus, Brazil
- Faculdade de Medicina, Universidade Nilton Lins, Manaus, Brazil
| | - Elsa Du Bruyn
- Wellcome Centre for Infectious Disease Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa
| | - Catherine Riou
- Wellcome Centre for Infectious Disease Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa
| | - Kate Aberman
- Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD
| | - Robert John Wilkinson
- Wellcome Centre for Infectious Disease Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa
- The Francis Crick Institute, London, Northwick Park Hospital, Harrow, UK
- Department of Infectious Disease, Imperial College London, London, UK
| | - Daniel L. Barber
- T Lymphocyte Biology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD
| | - Katrin D. Mayer-Barber
- Inflammation and Innate Immunity Unit, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD
| | - Bruno B. Andrade
- Laboratório de Inflamação e Biomarcadores, Instituto Gonçalo Moniz, Fundação Oswaldo Cruz, Salvador, Bahia, Brazil
- Multinational Organization Network Sponsoring Translational and Epidemiological Research Initiative, Salvador, Brazil
- Curso de Medicina, Universidade Salvador, Laureate Universities, Salvador, Brazil
- Curso de Medicina, Escola Bahiana de Medicina e Saúde Pública, Salvador, Bahia, Brazil
- Faculdade de Medicina, Universidade Federal da Bahia, Salvador, Brazil
- Curso de Medicina, Universidade Faculdade de Tecnologia e Ciências, Salvador, Bahia, Brazil
- Division of Infectious Diseases, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN
| | - Alan Sher
- Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD
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31
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Zhao C, Bao L, Qiu M, Wu K, Zhao Y, Feng L, Xiang K, Zhang N, Hu X, Fu Y. Commensal cow Roseburia reduces gut-dysbiosis-induced mastitis through inhibiting bacterial translocation by producing butyrate in mice. Cell Rep 2022; 41:111681. [DOI: 10.1016/j.celrep.2022.111681] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Revised: 06/17/2022] [Accepted: 10/26/2022] [Indexed: 11/23/2022] Open
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Toyoda T, Hashimoto K, Ogawa Y, Tohyama M, Muto Y, Murashima T, Akao K, Honma K, Tanaka A. Immunohistological analysis of pathogenic infiltrates in the epidermis and liver of a patient with toxic epidermal necrolysis accompanied by vanishing bile duct syndrome. J Dermatol 2022; 49:1343-1347. [PMID: 36176039 DOI: 10.1111/1346-8138.16576] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Revised: 08/11/2022] [Accepted: 08/23/2022] [Indexed: 11/29/2022]
Abstract
Toxic epidermal necrolysis (TEN) is a severe cutaneous adverse drug reaction characterized by extensive epidermal detachment, which is reportedly mediated by drug-specific cytotoxic CD8+ T cells, inflammatory monocytes, and neutrophils. Besides the skin, TEN often damages other organs, and it remains unknown whether they are mediated by similar pathogenic cells that cause epidermal damage. We experienced a case who developed TEN complicated with vanishing bile duct syndrome. Immunohistological analysis revealed the infiltration of CD8+ T cells, inflammatory monocytes, and neutrophil extracellular trap-forming neutrophils in the lesions of both the skin and liver with different degree of infiltration of these cells. These data suggest a difference of dominant pathogenic cells between skin and liver of patients with TEN.
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Affiliation(s)
- Tomohiro Toyoda
- Department of Dermatology, Kameda Medical Center, Chiba, Japan
| | - Koji Hashimoto
- Department of Dermatology, Kameda Medical Center, Chiba, Japan
| | - Youichi Ogawa
- Department of Dermatology, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Mikiko Tohyama
- Department of Dermatology, Shikoku Cancer Center, Ehime, Japan
| | - Yoshinori Muto
- Department of Dermatology, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
| | | | - Kei Akao
- Department of Dermatology, Kameda Medical Center, Chiba, Japan
| | - Koichi Honma
- Department of Pathology, Kameda Medical Center, Chiba, Japan
| | - Atsushi Tanaka
- Department of Dermatology, Kameda Medical Center, Chiba, Japan
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33
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Oliveira THC, Vanheule V, Vandendriessche S, Poosti F, Teixeira MM, Proost P, Gouwy M, Marques PE. The GAG-Binding Peptide MIG30 Protects against Liver Ischemia-Reperfusion in Mice. Int J Mol Sci 2022; 23:ijms23179715. [PMID: 36077113 PMCID: PMC9456047 DOI: 10.3390/ijms23179715] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Revised: 08/18/2022] [Accepted: 08/23/2022] [Indexed: 11/24/2022] Open
Abstract
Ischemia-reperfusion injury (IRI) drives graft rejection and is the main cause of mortality after liver transplantation. During IRI, an intense inflammatory response marked by chemokine production and neutrophil recruitment occurs. However, few strategies are available to restrain this excessive response. Here, we aimed to interfere with chemokine function during IRI in order to disrupt neutrophil recruitment to the injured liver. For this, we utilized a potent glycosaminoglycan (GAG)-binding peptide containing the 30 C-terminal amino acids of CXCL9 (MIG30) that is able to inhibit the binding of chemokines to GAGs in vitro. We observed that mice subjected to IRI and treated with MIG30 presented significantly lower liver injury and dysfunction as compared to vehicle-treated mice. Moreover, the levels of chemokines CXCL1, CXCL2 and CXCL6 and of proinflammatory cytokines TNF-α and IL-6 were significantly reduced in MIG30-treated mice. These events were associated with a marked inhibition of neutrophil recruitment to the liver during IRI. Lastly, we observed that MIG30 is unable to affect leukocytes directly nor to alter the stimulation by either CXCL8 or lipopolysaccharide (LPS), suggesting that its protective properties derive from its ability to inhibit chemokine activity in vivo. We conclude that MIG30 holds promise as a strategy to treat liver IRI and inflammation.
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Affiliation(s)
- Thiago Henrique Caldeira Oliveira
- Immunopharmacology Laboratory, Department of Biochemistry and Immunology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, Brazil
- Laboratory of Molecular Immunology, Department of Microbiology, Rega Institute, Immunology and Transplantation, KU Leuven, 3000 Leuven, Belgium
| | - Vincent Vanheule
- Laboratory of Molecular Immunology, Department of Microbiology, Rega Institute, Immunology and Transplantation, KU Leuven, 3000 Leuven, Belgium
| | - Sofie Vandendriessche
- Laboratory of Molecular Immunology, Department of Microbiology, Rega Institute, Immunology and Transplantation, KU Leuven, 3000 Leuven, Belgium
| | - Fariba Poosti
- Laboratory of Molecular Immunology, Department of Microbiology, Rega Institute, Immunology and Transplantation, KU Leuven, 3000 Leuven, Belgium
| | - Mauro Martins Teixeira
- Immunopharmacology Laboratory, Department of Biochemistry and Immunology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, Brazil
| | - Paul Proost
- Laboratory of Molecular Immunology, Department of Microbiology, Rega Institute, Immunology and Transplantation, KU Leuven, 3000 Leuven, Belgium
| | - Mieke Gouwy
- Laboratory of Molecular Immunology, Department of Microbiology, Rega Institute, Immunology and Transplantation, KU Leuven, 3000 Leuven, Belgium
| | - Pedro Elias Marques
- Laboratory of Molecular Immunology, Department of Microbiology, Rega Institute, Immunology and Transplantation, KU Leuven, 3000 Leuven, Belgium
- Correspondence:
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34
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Sun X, Wu J, Liu L, Chen Y, Tang Y, Liu S, Chen H, Jiang Y, Liu Y, Yuan H, Lu Y, Chen Z, Cai J. Transcriptional switch of hepatocytes initiates macrophage recruitment and T-cell suppression in endotoxemia. J Hepatol 2022; 77:436-452. [PMID: 35276271 DOI: 10.1016/j.jhep.2022.02.028] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Revised: 02/06/2022] [Accepted: 02/17/2022] [Indexed: 12/15/2022]
Abstract
BACKGROUND & AIMS The liver plays crucial roles in the regulation of immune defense during acute systemic infections. However, the roles of liver cellular clusters and intercellular communication in the progression of endotoxemia have not been well-characterized. METHODS Single-cell RNA sequencing analysis was performed, and the transcriptomes of 19,795 single liver cells from healthy and endotoxic mice were profiled. The spatial and temporal changes in hepatocytes and non-parenchymal cell types were validated by multiplex immunofluorescence staining, bulk transcriptomic sequencing, or flow cytometry. Furthermore, we used an adeno-associated virus delivery system to confirm the major mechanisms mediating myeloid cell infiltration and T-cell suppression in septic murine liver. RESULTS We identified a proinflammatory hepatocyte (PIH) subpopulation that developed primarily from periportal hepatocytes and to a lesser extent from pericentral hepatocytes and played key immunoregulatory roles in endotoxemia. Multicellular cluster modeling of ligand-receptor interactions revealed that PIHs play a crucial role in the recruitment of macrophages via the CCL2-CCR2 interaction. Recruited macrophages (RMs) released cytokines (e.g., IL6, TNFα, and IL17) to induce the expression of inhibitory ligands, such as PD-L1, on hepatocytes. Subsequently, RM-stimulated hepatocytes led to the suppression of CD4+ and memory T-cell subsets partly via the PD-1/PD-L1 interaction in endotoxemia. Furthermore, sinusoidal endothelial cells expressed the highest levels of proapoptotic and inflammatory genes around the periportal zone. This pattern of gene expression facilitated increases in the number of fenestrations and infiltration of immune cells in the periportal zone. CONCLUSIONS Our study elucidates unanticipated aspects of the cellular and molecular effects of endotoxemia on liver cells at the single-cell level and provides a conceptual framework for the development of novel therapeutic approaches for acute infection. LAY SUMMARY The liver plays a crucial role in the regulation of immune defense during acute systemic infections. We identified a proinflammatory hepatocyte subpopulation and demonstrated that the interactions of this subpopulation with recruited macrophages are pivotal in the immune response during endotoxemia. These novel findings provide a conceptual framework for the discovery of rational therapeutic targets in acute infection.
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Affiliation(s)
- Xuejing Sun
- Department of Cardiology, The Third Xiangya Hospital, Central South University, Changsha 410013, China
| | - Junru Wu
- Department of Cardiology, The Third Xiangya Hospital, Central South University, Changsha 410013, China
| | - Lun Liu
- Department of Cardiology, The Third Xiangya Hospital, Central South University, Changsha 410013, China
| | - Yuanyuan Chen
- Department of Cardiology, The Third Xiangya Hospital, Central South University, Changsha 410013, China
| | - Yan Tang
- Department of Cardiology, The Third Xiangya Hospital, Central South University, Changsha 410013, China
| | - Suzhen Liu
- Department of Cardiology, The Third Xiangya Hospital, Central South University, Changsha 410013, China
| | - Hang Chen
- Department of Cardiology, Fujian Medical Center for Cardiovascular Diseases, Fujian Medical University Union Hospital, Fuzhou, Fujian, P.R. China
| | - Youxiang Jiang
- Department of Cardiology, The Third Xiangya Hospital, Central South University, Changsha 410013, China
| | - Yuanyuan Liu
- The Center of Clinical Pharmacology, The Third Xiangya Hospital, Central South University, Changsha 410013, China
| | - Hong Yuan
- Department of Cardiology, The Third Xiangya Hospital, Central South University, Changsha 410013, China; The Center of Clinical Pharmacology, The Third Xiangya Hospital, Central South University, Changsha 410013, China
| | - Yao Lu
- The Center of Clinical Pharmacology, The Third Xiangya Hospital, Central South University, Changsha 410013, China
| | - Zhaoyang Chen
- Department of Cardiology, Fujian Medical Center for Cardiovascular Diseases, Fujian Medical University Union Hospital, Fuzhou, Fujian, P.R. China.
| | - Jingjing Cai
- Department of Cardiology, The Third Xiangya Hospital, Central South University, Changsha 410013, China; The Center of Clinical Pharmacology, The Third Xiangya Hospital, Central South University, Changsha 410013, China.
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Lopes ME, Nakagaki BN, Mattos MS, Campolina-Silva GH, Meira RDO, Paixão P, Oliveira A, Faustino L, Gonçalves R, Menezes GB. Susceptibility to Infections During Acute Liver Injury Depends on Transient Disruption of Liver Macrophage Niche. Front Immunol 2022; 13:892114. [PMID: 35967353 PMCID: PMC9368782 DOI: 10.3389/fimmu.2022.892114] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Accepted: 06/20/2022] [Indexed: 11/25/2022] Open
Abstract
Kupffer cells are the primary liver resident immune cell responsible for the liver firewall function, including clearance of bacterial infection from the circulation, as they are strategically positioned inside the liver sinusoid with intimate contact with the blood. Disruption in the tissue-resident macrophage niche, such as in Kupffer cells, can lead to a window of susceptibility to systemic infections, which represents a significant cause of mortality in patients with acetaminophen (APAP) overdose-induced acute liver injury (ALI). However, how Kupffer cell niche disruption increases susceptibility to systemic infections in ALI is not fully understood. Using a mouse model of ALI induced by APAP overdose, we found that Kupffer cells upregulated the apoptotic cell death program and were markedly reduced in the necrotic areas during the early stages of ALI, opening the niche for the infiltration of neutrophils and monocyte subsets. In addition, during the resolution phase of ALI, the remaining tissue macrophages with a Kupffer cell morphology were observed forming replicating cell clusters closer to necrotic areas devoid of Kupffer cells. Interestingly, mice with APAP-induced liver injury were still susceptible to infections despite the dual cellular input of circulating monocytes and proliferation of remaining Kupffer cells in the damaged liver. Therapy with bone marrow-derived macrophages (BMDM) was shown to be effective in occupying the niche devoid of Kupffer cells following APAP-induced ALI. The rapid BMDM migration to the liver and their positioning within necrotic areas enhanced the healing of the tissue and restored the liver firewall function after BMDM therapy. Therefore, we showed that disruption in the Kupffer cell niche and its impaired function during acute liver injury are key factors for the susceptibility to systemic bacterial infections. In addition, modulation of the liver macrophage niche was shown to be a promising therapeutic strategy for liver injuries that reduce the Kupffer cell number and compromise the organ function.
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Affiliation(s)
- Mateus Eustáquio Lopes
- Center for Gastrointestinal Biology, Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil
- *Correspondence: Mateus Eustáquio Lopes, ; Gustavo Batista Menezes,
| | - Brenda Naemi Nakagaki
- Center for Gastrointestinal Biology, Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil
| | - Matheus Silvério Mattos
- Center for Gastrointestinal Biology, Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil
| | - Gabriel Henrique Campolina-Silva
- Department of Biochemistry and Immunology, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil
- Centre de Recherche du Centre Hospitalier Universitaire de Québec, Université Laval, Québec, QC, Canada
| | - Raquel de Oliveira Meira
- Macrophage and Monocyte Biology Laboratory, Department of Pathology, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil
| | - Pierre Henrique de Menezes Paixão
- Macrophage and Monocyte Biology Laboratory, Department of Pathology, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil
| | - André Gustavo Oliveira
- Department of Physiology and Biophysics, Instituto de Ciências Biológicas, Universidade
Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil
| | - Lucas D. Faustino
- Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
| | - Ricardo Gonçalves
- Macrophage and Monocyte Biology Laboratory, Department of Pathology, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil
| | - Gustavo Batista Menezes
- Center for Gastrointestinal Biology, Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil
- *Correspondence: Mateus Eustáquio Lopes, ; Gustavo Batista Menezes,
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36
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Abbas AA, Hamdy A, Ahmed AE. Compromised blood-bile barrier after acetaminophen overdose. Arch Toxicol 2022; 96:2825-2827. [PMID: 35849165 DOI: 10.1007/s00204-022-03335-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Accepted: 07/07/2022] [Indexed: 11/26/2022]
Abstract
N-acetylcysteine (NAC) is the only approved drug for the treatment of acetaminophen (APAP) intoxication. A limitation of NAC is the short therapeutic time-window as it is only effective within approximately eight hours after APAP ingestion, which is critical since patients seek medical attention often after the onset of symptoms approximately 24 h after overdose. Recently, a so far unknown mechanism was identified by which APAP causes an increase of intracellular bile acid concentrations in hepatocytes to concentrations that exceed cytotoxic thresholds. APAP compromises the tight junctions of bile canaliculi that leads to the leakage of highly concentrated bile acids into the sinusoids. From the sinusoidal blood, a high fraction of the released bile acids is transported back into hepatocytes by basolateral uptake carriers and secreted into bile canaliculi. Repeated leakage from the canaliculi followed by hepatocellular reuptake and canalicular secretion causes an increase of intracellular bile acid concentrations and finally hepatocyte death. Importantly, inhibition of bile acid uptake carriers reduced intracellular bile acid concentrations and strongly ameliorated APAP hepatotoxicity, a finding that could result in a new therapeutic option for APAP-intoxicated patients.
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Affiliation(s)
- Aya A Abbas
- Forensic Medicine and Toxicology Department, Faculty of Veterinary Medicine, South Valley University, Qena, 83523, Egypt
| | - Amira Hamdy
- Forensic Medicine and Toxicology Department, Faculty of Veterinary Medicine, South Valley University, Qena, 83523, Egypt
| | - Ahmed Ezzat Ahmed
- Department of Theriogenology, Faculty of Veterinary Medicine, South Valley University, Qena, 83523, Egypt.
- Department of Biology, College of Science, King Khalid University, Abha, 61413, Asir, Saudi Arabia.
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Yen NTH, Park SM, Thu VTA, Phat NK, Cho YS, Yoon S, Shin JG, Kim DH, Oh JH, Long NP. Genome-wide gene expression analysis reveals molecular insights into the drug-induced toxicity of nephrotoxic agents. Life Sci 2022; 306:120801. [PMID: 35850247 DOI: 10.1016/j.lfs.2022.120801] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Revised: 06/30/2022] [Accepted: 07/09/2022] [Indexed: 11/17/2022]
Abstract
Drug-induced nephrotoxicity is frequently reported. However, the mechanisms underlying nephrotoxic medications and their overlapping molecular events, which might have therapeutic value, are unclear. We performed a genome-wide analysis of gene expression and a gene set enrichment analysis to identify common and unique pathways associated with the toxicity of colistin, ifosfamide, indomethacin, and puromycin. Rats were randomly allocated into the treatment or control group. The treatment group received a toxic dose once daily of each investigated drug for 1 week. Differentially expressed genes were found in the drug-treated kidney and liver compared to the control, except for colistin in the liver. Upregulated pathways were mainly related to cell death, cell cycle, protein synthesis, and immune response modulation in the kidney. Cell cycle was upregulated by all drugs. Downregulated pathways were associated with carbon metabolism, amino acid metabolism, and fatty acid metabolism. Indomethacin, colistin, and puromycin shared the most altered pathways in the kidney. Ifosfamide and indomethacin affected molecular processes greatly in the liver. Our findings provide insight into the mechanisms underlying the renal and hepatic adverse effects of the four drugs. Further investigation should explore the combinatory drug therapies that attenuate the toxic effects and maximize the effectiveness of nephrotoxic drugs.
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Affiliation(s)
- Nguyen Thi Hai Yen
- Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine, Busan 614-735, Republic of Korea; Center for Personalized Precision Medicine of Tuberculosis, Inje University College of Medicine, Busan 614-735, Republic of Korea
| | - Se-Myo Park
- Department of Predictive Toxicology, Korea Institute of Toxicology, Daejeon 34114, Republic of Korea
| | - Vo Thuy Anh Thu
- Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine, Busan 614-735, Republic of Korea; Center for Personalized Precision Medicine of Tuberculosis, Inje University College of Medicine, Busan 614-735, Republic of Korea
| | - Nguyen Ky Phat
- Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine, Busan 614-735, Republic of Korea; Center for Personalized Precision Medicine of Tuberculosis, Inje University College of Medicine, Busan 614-735, Republic of Korea
| | - Yong-Soon Cho
- Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine, Busan 614-735, Republic of Korea; Center for Personalized Precision Medicine of Tuberculosis, Inje University College of Medicine, Busan 614-735, Republic of Korea
| | - Seokjoo Yoon
- Department of Predictive Toxicology, Korea Institute of Toxicology, Daejeon 34114, Republic of Korea
| | - Jae-Gook Shin
- Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine, Busan 614-735, Republic of Korea; Center for Personalized Precision Medicine of Tuberculosis, Inje University College of Medicine, Busan 614-735, Republic of Korea
| | - Dong Hyun Kim
- Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine, Busan 614-735, Republic of Korea
| | - Jung-Hwa Oh
- Department of Predictive Toxicology, Korea Institute of Toxicology, Daejeon 34114, Republic of Korea.
| | - Nguyen Phuoc Long
- Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine, Busan 614-735, Republic of Korea; Center for Personalized Precision Medicine of Tuberculosis, Inje University College of Medicine, Busan 614-735, Republic of Korea.
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38
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Kmeťová K, Drobná D, Lipták R, Hodosy J, Celec P. Early dynamics of glial fibrillary acidic protein and extracellular DNA in plasma of mice after closed head traumatic brain injury. Neurochirurgie 2022; 68:e68-e74. [PMID: 35810032 DOI: 10.1016/j.neuchi.2022.06.003] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Revised: 04/28/2022] [Accepted: 06/07/2022] [Indexed: 11/30/2022]
Abstract
BACKGROUND Glial fibrillary acidic protein (GFAP) in plasma is an established biomarker of traumatic brain injury (TBI) in humans. Plasma extracellular DNA (ecDNA) is a very sensitive, although nonspecific marker of tissue damage including TBI. Whether plasma GFAP or ecDNA could be used as an early non-invasive biomarker in the mouse model of closed head injury is unknown. The aim of this paper was to describe the early dynamics of plasma GFAP and ecDNA in the animal model of closed head TBI. METHODS Closed head TBI was induced using the weight-drop method in 40 adult CD1 mice and blood was collected in different time points (1, 2 or 3h) after TBI in different groups of mice. Plasma GFAP and ecDNA and ecDNA fragmentation from the experimental groups were compared to healthy controls. In the surviving mice, a static rods test was performed 30 days after TBI to assess the neurological outcome of TBI. RESULTS Despite a trend of higher plasma GFAP after TBI the differences between the groups were not statistically significant. Plasma ecDNA was higher by 50% after 1h (P<0.05) and 2h (P<0.05) after TBI and was highly variable after 3h. Plasma ecDNA, but not GFAP, was partially predictive of the neurological impairment of the mice. CONCLUSION In this study, we have described the early dynamics of plasma GFAP and ecDNA after TBI in mice. According to our results, ecDNA in plasma is a more sensitive early marker of TBI than GFAP. Analysis of tissue-specific ecDNA might improve its predictive value regarding the survival and neurobehavioral outcome.
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Affiliation(s)
- K Kmeťová
- Institute of Molecular Biomedicine, Faculty of Medicine, Comenius University, Bratislava, Slovakia.
| | - D Drobná
- Institute of Molecular Biomedicine, Faculty of Medicine, Comenius University, Bratislava, Slovakia.
| | - R Lipták
- Institute of Molecular Biomedicine, Faculty of Medicine, Comenius University, Bratislava, Slovakia; Emergency Department, University Hospital Bratislava, Bratislava, Slovakia; Institute of Physiology, Faculty of Medicine, Comenius University, Bratislava, Slovakia.
| | - J Hodosy
- Institute of Molecular Biomedicine, Faculty of Medicine, Comenius University, Bratislava, Slovakia; Emergency Department, University Hospital Bratislava, Bratislava, Slovakia; Institute of Physiology, Faculty of Medicine, Comenius University, Bratislava, Slovakia.
| | - P Celec
- Institute of Molecular Biomedicine, Faculty of Medicine, Comenius University, Bratislava, Slovakia; Institute of Pathophysiology, Faculty of Medicine, Comenius University, Bratislava, Slovakia; Institute of Molecular Biology, Faculty of Natural Sciences, Comenius University, Bratislava, Slovakia.
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Wang J, Zhang L, Shi Q, Yang B, He Q, Wang J, Weng Q. Targeting innate immune responses to attenuate acetaminophen-induced hepatotoxicity. Biochem Pharmacol 2022; 202:115142. [PMID: 35700755 DOI: 10.1016/j.bcp.2022.115142] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Revised: 06/06/2022] [Accepted: 06/07/2022] [Indexed: 11/02/2022]
Abstract
Acetaminophen (APAP) hepatotoxicity is an important cause of acute liver failure, resulting in massive deaths in many developed countries. Currently, the metabolic process of APAP in the body has been well studied. However, the underlying mechanism of APAP-induced liver injury remains elusive. Increasing clinical and experimental evidences indicate that the innate immune responses are involved in the pathogenesis of APAP-induced acute liver injury (AILI), in which immune cells have dual roles of inducing inflammation to exacerbate hepatotoxicity and removing dead cells and debris to help liver regeneration. In this review, we summarize the latest findings of innate immune cells involved in AILI, particularly emphasizing the activation of innate immune cells and their different roles during the injury and repair phases. Moreover, current available treatments are discussed according to the different roles of innate immune cells in the development of AILI. This review aims to update the knowledge about innate immune responses in the pathogenesis of AILI, and provide potential therapeutic interventions for AILI.
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Affiliation(s)
- Jincheng Wang
- Center for Drug Safety Evaluation and Research, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Lulu Zhang
- Center for Drug Safety Evaluation and Research, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Qi Shi
- Center for Drug Safety Evaluation and Research, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; Hangzhou Institute of Innovative Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Bo Yang
- Center for Drug Safety Evaluation and Research, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Qiaojun He
- Center for Drug Safety Evaluation and Research, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; Hangzhou Institute of Innovative Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Jiajia Wang
- Center for Drug Safety Evaluation and Research, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; Hangzhou Institute of Innovative Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
| | - Qinjie Weng
- Center for Drug Safety Evaluation and Research, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; Hangzhou Institute of Innovative Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China.
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von Meijenfeldt FA, Stravitz RT, Zhang J, Adelmeijer J, Zen Y, Durkalski V, Lee W, Lisman T. Generation of neutrophil extracellular traps in patients with acute liver failure is associated with poor outcome. Hepatology 2022; 75:623-633. [PMID: 34562318 PMCID: PMC9299791 DOI: 10.1002/hep.32174] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2020] [Revised: 08/11/2021] [Accepted: 09/09/2021] [Indexed: 12/18/2022]
Abstract
BACKGROUND AND AIMS Acute liver failure (ALF) is characterized by significant changes in the hemostatic system and by systemic inflammation. The formation of neutrophil extracellular traps (NETs), in which an activated neutrophil expels its DNA, histones, and granular enzymes, such as myeloperoxidase (MPO), has been associated with immune-mediated and thrombotic diseases. We hypothesized that formation of NETs in patients with ALF contributes to progression of disease. APPROACH AND RESULTS A total of 676 patients with ALF (international normalized ratio [INR], ≥1.5) or severe acute liver injury (ALI; INR, ≥2.0) were recruited from the U.S. ALF Study Group Registry between 2011 and 2018, of whom 308 patients (45.6%) had acetaminophen-induced ALF. Up to 21 days after admission, 483 patients (71.5%) survived without liver transplantation (LT). Levels of cell-free DNA (cfDNA) and the specific NET marker MPO-DNA complexes were measured in plasma samples obtained on admission and compared to levels in healthy controls. In addition, liver tissue obtained at transplantation of 20 ALF patients was stained for NETs. Levels of cfDNA were 7.1-fold, and MPO-DNA complexes 2.5-fold, higher in patients with ALF compared to healthy controls. cfDNA levels were not associated with 21-day transplant-free survival, but were higher in those patients with more-severe disease on admission, as reflected by various laboratory and clinical parameters. MPO-DNA levels were 30% higher in patients with ALF who died or required urgent LT. Liver tissue of ALF patients stained positive for NETs in 12 of 18 evaluable patients. CONCLUSIONS Here, we provide evidence for NET formation in patients with ALF. Elevated plasma levels of MPO-DNA complexes in patients with ALF were associated with poor outcome, which suggests that NET formation contributes to disease progression.
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Affiliation(s)
- Fien A. von Meijenfeldt
- Surgical Research LaboratoryDepartment of SurgeryUniversity of GroningenUniversity Medical Center GroningenGroningenThe Netherlands
| | - R. Todd Stravitz
- Hume‐Lee Transplant Center of Virginia Commonwealth UniversityRichmondVirginiaUSA
| | - Jingwen Zhang
- Department of Public Health SciencesMedical University of South CarolinaCharlestonSouth CarolinaUSA
| | - Jelle Adelmeijer
- Surgical Research LaboratoryDepartment of SurgeryUniversity of GroningenUniversity Medical Center GroningenGroningenThe Netherlands
| | - Yoh Zen
- Department of PathologyInstitute of Liver StudiesKing’s College HospitalLondonUK
| | - Valerie Durkalski
- Department of Public Health SciencesMedical University of South CarolinaCharlestonSouth CarolinaUSA
| | - William M. Lee
- University of Texas‐Southwestern Medical CenterDallasTexasUSA
| | - Ton Lisman
- Surgical Research LaboratoryDepartment of SurgeryUniversity of GroningenUniversity Medical Center GroningenGroningenThe Netherlands
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Papachristoforou E, Ramachandran P. Macrophages as key regulators of liver health and disease. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2022; 368:143-212. [PMID: 35636927 DOI: 10.1016/bs.ircmb.2022.04.006] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Macrophages are a heterogeneous population of innate immune cells and key cellular components of the liver. Hepatic macrophages consist of embryologically-derived resident Kupffer cells (KC), recruited monocyte-derived macrophages (MDM) and capsular macrophages. Both the diversity and plasticity of hepatic macrophage subsets explain their different functions in the maintenance of hepatic homeostasis and in injury processes in acute and chronic liver diseases. In this review, we assess the evidence for macrophage involvement in regulating both liver health and injury responses in liver diseases including acute liver injury (ALI), chronic liver disease (CLD) (including liver fibrosis) and hepatocellular carcinoma (HCC). In healthy livers, KC display critical functions such as phagocytosis, danger signal recognition, cytokine release, antigen processing and the ability to orchestrate immune responses and maintain immunological tolerance. However, in most liver diseases there is a striking hepatic MDM expansion, which orchestrate both disease progression and regression. Single-cell approaches have transformed our understanding of liver macrophage heterogeneity, dynamics, and functions in both human samples and preclinical models. We will further discuss the new insights provided by these approaches and how they are enabling high-fidelity work to specifically identify pathogenic macrophage subpopulations. Given the important role of macrophages in regulating injury responses in a broad range of settings, there is now a huge interest in developing new therapeutic strategies aimed at targeting macrophages. Therefore, we also review the current approaches being used to modulate macrophage function in liver diseases and discuss the therapeutic potential of targeting macrophage subpopulations as a novel treatment strategy for patients with liver disorders.
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Affiliation(s)
- Eleni Papachristoforou
- University of Edinburgh Centre for Inflammation Research, The Queen's Medical Research Institute, Edinburgh BioQuarter, Edinburgh, United Kingdom
| | - Prakash Ramachandran
- University of Edinburgh Centre for Inflammation Research, The Queen's Medical Research Institute, Edinburgh BioQuarter, Edinburgh, United Kingdom.
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Jaeschke H, Adelusi OB, Akakpo JY, Nguyen NT, Sanchez-Guerrero G, Umbaugh DS, Ding WX, Ramachandran A. Recommendations for the use of the acetaminophen hepatotoxicity model for mechanistic studies and how to avoid common pitfalls. Acta Pharm Sin B 2021; 11:3740-3755. [PMID: 35024303 PMCID: PMC8727921 DOI: 10.1016/j.apsb.2021.09.023] [Citation(s) in RCA: 77] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Revised: 08/22/2021] [Accepted: 09/10/2021] [Indexed: 02/07/2023] Open
Abstract
Acetaminophen (APAP) is a widely used analgesic and antipyretic drug, which is safe at therapeutic doses but can cause severe liver injury and even liver failure after overdoses. The mouse model of APAP hepatotoxicity recapitulates closely the human pathophysiology. As a result, this clinically relevant model is frequently used to study mechanisms of drug-induced liver injury and even more so to test potential therapeutic interventions. However, the complexity of the model requires a thorough understanding of the pathophysiology to obtain valid results and mechanistic information that is translatable to the clinic. However, many studies using this model are flawed, which jeopardizes the scientific and clinical relevance. The purpose of this review is to provide a framework of the model where mechanistically sound and clinically relevant data can be obtained. The discussion provides insight into the injury mechanisms and how to study it including the critical roles of drug metabolism, mitochondrial dysfunction, necrotic cell death, autophagy and the sterile inflammatory response. In addition, the most frequently made mistakes when using this model are discussed. Thus, considering these recommendations when studying APAP hepatotoxicity will facilitate the discovery of more clinically relevant interventions.
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Key Words
- AIF, apoptosis-inducing factor
- AMPK, AMP-activated protein kinase
- APAP, acetaminophen
- ARE, antioxidant response element
- ATG, autophagy-related genes
- Acetaminophen hepatotoxicity
- Apoptosis
- Autophagy
- BSO, buthionine sulfoximine
- CAD, caspase-activated DNase
- CYP, cytochrome P450 enzymes
- DAMPs, damage-associated molecular patterns
- DMSO, dimethylsulfoxide
- Drug metabolism
- EndoG, endonuclease G
- FSP1, ferroptosis suppressing protein 1
- Ferroptosis
- GPX4, glutathione peroxidase 4
- GSH, glutathione
- GSSG, glutathione disulfide
- Gclc, glutamate–cysteine ligase catalytic subunit
- Gclm, glutamate–cysteine ligase modifier subunit
- HMGB1, high mobility group box protein 1
- HNE, 4-hydroxynonenal
- Innate immunity
- JNK, c-jun N-terminal kinase
- KEAP1, Kelch-like ECH-associated protein 1
- LAMP, lysosomal-associated membrane protein
- LC3, light chain 3
- LOOH, lipid hydroperoxides
- LPO, lipid peroxidation
- MAP kinase, mitogen activated protein kinase
- MCP-1, monocyte chemoattractant protein-1
- MDA, malondialdehyde
- MPT, mitochondrial permeability transition
- Mitochondria
- MnSOD, manganese superoxide dismutase
- NAC, N-acetylcysteine
- NAPQI, N-acetyl-p-benzoquinone imine
- NF-κB, nuclear factor κB
- NQO1, NAD(P)H:quinone oxidoreductase 1
- NRF2
- NRF2, nuclear factor erythroid 2-related factor 2
- PUFAs, polyunsaturated fatty acids
- ROS, reactive oxygen species
- SMAC/DIABLO, second mitochondria-derived activator of caspase/direct inhibitor of apoptosis-binding protein with low pI
- TLR, toll like receptor
- TUNEL, terminal deoxynucleotidyl transferase dUTP nick end labeling
- UGT, UDP-glucuronosyltransferases
- mTORC1, mammalian target of rapamycin complex 1
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Affiliation(s)
- Hartmut Jaeschke
- Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Olamide B. Adelusi
- Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Jephte Y. Akakpo
- Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Nga T. Nguyen
- Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Giselle Sanchez-Guerrero
- Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - David S. Umbaugh
- Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Wen-Xing Ding
- Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Anup Ramachandran
- Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
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Mitochondrial Mechanisms of Apoptosis and Necroptosis in Liver Diseases. Anal Cell Pathol (Amst) 2021; 2021:8900122. [PMID: 34804779 PMCID: PMC8601834 DOI: 10.1155/2021/8900122] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Revised: 10/20/2021] [Accepted: 10/26/2021] [Indexed: 12/23/2022] Open
Abstract
In addition to playing a pivotal role in cellular energetics and biosynthesis, mitochondrial components are key operators in the regulation of cell death. In addition to apoptosis, necrosis is a highly relevant form of programmed liver cell death. Differential activation of specific forms of programmed cell death may not only affect the outcome of liver disease but may also provide new opportunities for therapeutic intervention. This review describes the role of mitochondria in cell death and the mechanism that leads to chronic liver hepatitis and liver cirrhosis. We focus on mitochondrial-driven apoptosis and current knowledge of necroptosis and discuss therapeutic strategies for targeting mitochondrial-mediated cell death in liver diseases.
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Oliveira-Costa KM, Menezes GB, Paula Neto HA. Neutrophil accumulation within tissues: A damage x healing dichotomy. Biomed Pharmacother 2021; 145:112422. [PMID: 34781139 DOI: 10.1016/j.biopha.2021.112422] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Revised: 11/08/2021] [Accepted: 11/10/2021] [Indexed: 02/09/2023] Open
Abstract
The abundance of neutrophils in human circulation, their fast mobilization from blood to tissues, along with their alleged short life-span led to the image of neutrophils as a homogeneous cell type designed to fight infections and die in the process. Additionally, their granule content and capacity to produce molecules with considerable cytotoxic potential, lead to the general belief that neutrophil activation inexorably results in side effect of extensive tissue injury. Neutrophil activation in fact causes tissue injury as an adverse effect, but it seems that this is restricted to particular pathological situations and more of an "exception to the rule". Here we review evidences arising especially from intravital microscopy studies that demonstrate neutrophils as cells endowed with sophisticated mechanisms and able to engage in complex interactions as to minimize damage and optimize their effector functions. Moreover, neutrophil infiltration may even contribute to tissue healing and repair which may altogether demand a reexamination of current anti-inflammatory therapies that have neutrophil migration and activation as a target.
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Affiliation(s)
- Karen Marques Oliveira-Costa
- Center for Gastrointestinal Biology, Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais 31270-901, Brazil
| | - Gustavo B Menezes
- Center for Gastrointestinal Biology, Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais 31270-901, Brazil.
| | - Heitor A Paula Neto
- Laboratório de Alvos Moleculares, Departamento de Biotecnologia Farmacêutica, Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
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45
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Andrade ACDSP, Campolina-Silva GH, Queiroz-Junior CM, de Oliveira LC, Lacerda LDSB, Pimenta JC, de Souza FRO, de Meira Chaves I, Passos IB, Teixeira DC, Bittencourt-Silva PG, Valadão PAC, Rossi-Oliveira L, Antunes MM, Figueiredo AFA, Wnuk NT, Temerozo JR, Ferreira AC, Cramer A, Oliveira CA, Durães-Carvalho R, Weis Arns C, Guimarães PPG, Costa GMJ, de Menezes GB, Guatimosim C, da Silva GSF, Souza TML, Barrioni BR, Pereira MDM, de Sousa LP, Teixeira MM, Costa VV. A Biosafety Level 2 Mouse Model for Studying Betacoronavirus-Induced Acute Lung Damage and Systemic Manifestations. J Virol 2021; 95:e0127621. [PMID: 34495692 PMCID: PMC8549505 DOI: 10.1128/jvi.01276-21] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Accepted: 09/01/2021] [Indexed: 12/29/2022] Open
Abstract
The emergence of life-threatening zoonotic diseases caused by betacoronaviruses, including the ongoing coronavirus disease 19 (COVID-19) pandemic, has highlighted the need for developing preclinical models mirroring respiratory and systemic pathophysiological manifestations seen in infected humans. Here, we showed that C57BL/6J wild-type mice intranasally inoculated with the murine betacoronavirus murine hepatitis coronavirus 3 (MHV-3) develop a robust inflammatory response leading to acute lung injuries, including alveolar edema, hemorrhage, and fibrin thrombi. Although such histopathological changes seemed to resolve as the infection advanced, they efficiently impaired respiratory function, as the infected mice displayed restricted lung distention and increased respiratory frequency and ventilation. Following respiratory manifestation, the MHV-3 infection became systemic, and a high virus burden could be detected in multiple organs along with morphological changes. The systemic manifestation of MHV-3 infection was also marked by a sharp drop in the number of circulating platelets and lymphocytes, besides the augmented concentration of the proinflammatory cytokines interleukin 1 beta (IL-1β), IL-6, IL-12, gamma interferon (IFN-γ), and tumor necrosis factor (TNF), thereby mirroring some clinical features observed in moderate and severe cases of COVID-19. Importantly, both respiratory and systemic changes triggered by MHV-3 infection were greatly prevented by blocking TNF signaling, either via genetic or pharmacologic approaches. In line with this, TNF blockage also diminished the infection-mediated release of proinflammatory cytokines and virus replication of human epithelial lung cells infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Collectively, results show that MHV-3 respiratory infection leads to a large range of clinical manifestations in mice and may constitute an attractive, lower-cost, biosafety level 2 (BSL2) in vivo platform for evaluating the respiratory and multiorgan involvement of betacoronavirus infections. IMPORTANCE Mouse models have long been used as valuable in vivo platforms to investigate the pathogenesis of viral infections and effective countermeasures. The natural resistance of mice to the novel betacoronavirus SARS-CoV-2, the causative agent of COVID-19, has launched a race toward the characterization of SARS-CoV-2 infection in other animals (e.g., hamsters, cats, ferrets, bats, and monkeys), as well as adaptation of the mouse model, by modifying either the host or the virus. In the present study, we utilized a natural pathogen of mice, MHV, as a prototype to model betacoronavirus-induced acute lung injure and multiorgan involvement under biosafety level 2 conditions. We showed that C57BL/6J mice intranasally inoculated with MHV-3 develops severe disease, which includes acute lung damage and respiratory distress that precede systemic inflammation and death. Accordingly, the proposed animal model may provide a useful tool for studies regarding betacoronavirus respiratory infection and related diseases.
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Affiliation(s)
| | - Gabriel Henrique Campolina-Silva
- Department of Biochemistry and Immunology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - Celso Martins Queiroz-Junior
- Department of Morphology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - Leonardo Camilo de Oliveira
- Department of Morphology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | | | - Jordane C Pimenta
- Department of Morphology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | | | - Ian de Meira Chaves
- Department of Morphology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - Ingredy Beatriz Passos
- Department of Microbiology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - Danielle Cunha Teixeira
- Department of Morphology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - Paloma Graziele Bittencourt-Silva
- Department of Physiology and Biophysics, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | | | - Leonardo Rossi-Oliveira
- Department of Morphology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - Maisa Mota Antunes
- Department of Morphology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - André Felipe Almeida Figueiredo
- Department of Morphology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - Natália Teixeira Wnuk
- Department of Morphology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - Jairo R. Temerozo
- Laboratory on Thymus Research, Oswaldo Cruz Institute, Fiocruz, Rio de Janeiro, RJ, Brazil
- National Institute for Science and Technology on Neuroimmunomodulation, Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro, RJ, Brazil
| | - André Costa Ferreira
- National Institute for Science and Technology on Innovation on Diseases of Neglected Populations (INCT/IDNP), Center for Technological Development in Health (CDTS), Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro, RJ, Brazil
- Immunopharmacology Laboratory, Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro, RJ, Brazil
- Laboratório de Pesquisas Pré-clínicas, Universidade Iguaçu (UNIG), Rio de Janeiro, RJ, Brazil
| | - Allysson Cramer
- Department of Biochemistry and Immunology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - Cleida Aparecida Oliveira
- Department of Morphology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | | | - Clarice Weis Arns
- Laboratory of Virology, Universidade Estadual de Campinas (UNICAMP), Campinas, SP, Brazil
| | - Pedro Pires Goulart Guimarães
- Department of Physiology and Biophysics, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - Guilherme Mattos Jardim Costa
- Department of Morphology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - Gustavo Batista de Menezes
- Department of Morphology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - Cristina Guatimosim
- Department of Morphology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - Glauber Santos Ferreira da Silva
- Department of Physiology and Biophysics, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - Thiago Moreno L. Souza
- National Institute for Science and Technology on Innovation on Diseases of Neglected Populations (INCT/IDNP), Center for Technological Development in Health (CDTS), Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro, RJ, Brazil
- Immunopharmacology Laboratory, Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro, RJ, Brazil
| | - Breno Rocha Barrioni
- Department of Metallurgical Engineering and Materials, Federal University of Minas Gerais, School of Engineering, Belo Horizonte, Brazil
| | - Marivalda de Magalhães Pereira
- Department of Metallurgical Engineering and Materials, Federal University of Minas Gerais, School of Engineering, Belo Horizonte, Brazil
| | - Lirlândia Pires de Sousa
- Department of Clinical and Toxicological Analysis, Faculty of Pharmacy, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - Mauro Martins Teixeira
- Department of Biochemistry and Immunology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - Vivian Vasconcelos Costa
- Department of Morphology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
- Department of Biochemistry and Immunology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
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46
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Gong L, Liao L, Dai X, Xue X, Peng C, Li Y. The dual role of immune response in acetaminophen hepatotoxicity: Implication for immune pharmacological targets. Toxicol Lett 2021; 351:37-52. [PMID: 34454010 DOI: 10.1016/j.toxlet.2021.08.009] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Revised: 07/16/2021] [Accepted: 08/23/2021] [Indexed: 12/14/2022]
Abstract
Acetaminophen (APAP), one of the most widely used antipyretic and analgesic drugs, principally contributes to drug-induced liver injury when taken at a high dose. APAP-induced liver injury (AILI) results in extensive necrosis of hepatocytes along with the occurrence of multiple intracellular events such as metabolic activation, cell injury, and signaling pathway activation. However, the specific role of the immune response in AILI remains controversial for its complicated regulatory mechanisms. A variety of inflammasomes, immune cells, inflammatory mediators, and signaling transduction pathways are activated in AILI. These immune components play antagonistic roles in aggravating the liver injury or promoting regeneration. Recent experimental studies indicated that natural products showed remarkable therapeutic effects against APAP hepatotoxicity due to their favorable efficacy. Therefore, this study aimed to review the present understanding of the immune response in AILI and attempted to establish ties among a series of inflammatory cascade reactions. Also, the immune molecular mechanisms of natural products in the treatment of AILI were extensively reviewed, thus providing a fundamental basis for exploring the potential pharmacological targets associated with immune interventions.
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Affiliation(s)
- Lihong Gong
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Li Liao
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Xuyang Dai
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Xinyan Xue
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Cheng Peng
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China.
| | - Yunxia Li
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China.
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47
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Marques PE, Vandendriessche S, de Oliveira THC, Crijns H, Lopes ME, Blanter M, Schuermans S, Yu K, Poosti F, Vanheule V, Janssens R, Boff D, Kungl AJ, Menezes GB, Teixeira MM, Proost P. Inhibition of Drug-Induced Liver Injury in Mice Using a Positively Charged Peptide That Binds DNA. Hepatol Commun 2021; 5:1737-1754. [PMID: 34532999 PMCID: PMC8485890 DOI: 10.1002/hep4.1759] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Revised: 04/30/2021] [Accepted: 05/11/2021] [Indexed: 12/19/2022] Open
Abstract
Hepatic cell death occurs in response to diverse stimuli such as chemical and physical damage. The exposure of intracellular contents such as DNA during necrosis induces a severe inflammatory response that has yet to be fully explored therapeutically. Here, we sought means to neutralize the ability of extracellular DNA to induce deleterious tissue inflammation when drug-induced liver injury had already ensued. DNA exposure and inflammation were investigated in vivo in drug-induced liver injury using intravital microscopy. The necrotic DNA debris was studied in murine livers in vivo and in DNA debris models in vitro by using a positively charged chemokine-derived peptide (MIG30; CXCL9[74-103]). Acetaminophen-induced liver necrosis was associated with massive DNA accumulation, production of CXC chemokines, and neutrophil activation inside the injured tissue. The MIG30 peptide bound the healthy liver vasculature and, to a much greater extent, to DNA-rich necrotic tissue. Moreover, MIG30 bound extracellular DNA directly in vivo in a charge-dependent manner and independently of glycosaminoglycans and chemokines. Post-treatment of mice with MIG30 reduced mortality, liver damage, and inflammation significantly. These effects were not observed with a control peptide that does not bind DNA. Mechanistically, MIG30 inhibited the interaction between DNA and histones, and promoted the dissociation of histones from necrotic debris. MIG30 also inhibited the pro-inflammatory effect of CpG DNA, as measured by a reduction in CXCL8 production, indicating that MIG30 disturbs the ability of DNA to induce hepatic inflammation. Conclusion: The use of DNA-binding peptides reduces necrotic liver injury and inflammation, even at late timepoints.
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Affiliation(s)
- Pedro E Marques
- Laboratory of Molecular ImmunologyDepartment of Microbiology, Immunology and TransplantationRega Institute for Medical ResearchKU LeuvenLeuvenBelgium.,Immunopharmacology LaboratoryDepartment of Biochemistry and ImmunologyUniversidade Federal de Minas GeraisBelo HorizonteMinas GeraisBrazil
| | - Sofie Vandendriessche
- Laboratory of Molecular ImmunologyDepartment of Microbiology, Immunology and TransplantationRega Institute for Medical ResearchKU LeuvenLeuvenBelgium
| | - Thiago H C de Oliveira
- Laboratory of Molecular ImmunologyDepartment of Microbiology, Immunology and TransplantationRega Institute for Medical ResearchKU LeuvenLeuvenBelgium.,Immunopharmacology LaboratoryDepartment of Biochemistry and ImmunologyUniversidade Federal de Minas GeraisBelo HorizonteMinas GeraisBrazil
| | - Helena Crijns
- Laboratory of Molecular ImmunologyDepartment of Microbiology, Immunology and TransplantationRega Institute for Medical ResearchKU LeuvenLeuvenBelgium
| | - Mateus E Lopes
- Center for Gastrointestinal BiologyDepartment of MorphologyUniversidade Federal de Minas GeraisBelo HorizonteMinas GeraisBrazil
| | - Marfa Blanter
- Laboratory of Molecular ImmunologyDepartment of Microbiology, Immunology and TransplantationRega Institute for Medical ResearchKU LeuvenLeuvenBelgium
| | - Sara Schuermans
- Laboratory of Molecular ImmunologyDepartment of Microbiology, Immunology and TransplantationRega Institute for Medical ResearchKU LeuvenLeuvenBelgium
| | - Karen Yu
- Laboratory of Molecular ImmunologyDepartment of Microbiology, Immunology and TransplantationRega Institute for Medical ResearchKU LeuvenLeuvenBelgium
| | - Fariba Poosti
- Laboratory of Molecular ImmunologyDepartment of Microbiology, Immunology and TransplantationRega Institute for Medical ResearchKU LeuvenLeuvenBelgium
| | - Vincent Vanheule
- Laboratory of Molecular ImmunologyDepartment of Microbiology, Immunology and TransplantationRega Institute for Medical ResearchKU LeuvenLeuvenBelgium
| | - Rik Janssens
- Laboratory of Molecular ImmunologyDepartment of Microbiology, Immunology and TransplantationRega Institute for Medical ResearchKU LeuvenLeuvenBelgium
| | - Daiane Boff
- Laboratory of Molecular ImmunologyDepartment of Microbiology, Immunology and TransplantationRega Institute for Medical ResearchKU LeuvenLeuvenBelgium.,Immunopharmacology LaboratoryDepartment of Biochemistry and ImmunologyUniversidade Federal de Minas GeraisBelo HorizonteMinas GeraisBrazil
| | - Andreas J Kungl
- Department of Pharmaceutical ChemistryInstitute of Pharmaceutical SciencesKarl-Franzens UniversitätGrazAustria
| | - Gustavo B Menezes
- Center for Gastrointestinal BiologyDepartment of MorphologyUniversidade Federal de Minas GeraisBelo HorizonteMinas GeraisBrazil
| | - Mauro M Teixeira
- Immunopharmacology LaboratoryDepartment of Biochemistry and ImmunologyUniversidade Federal de Minas GeraisBelo HorizonteMinas GeraisBrazil
| | - Paul Proost
- Laboratory of Molecular ImmunologyDepartment of Microbiology, Immunology and TransplantationRega Institute for Medical ResearchKU LeuvenLeuvenBelgium
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48
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Li HY, Tang ZM, Wang Z, Lv JM, Liu XL, Liang YL, Cheng B, Gao N, Ji SR, Wu Y. C-Reactive Protein Protects Against Acetaminophen-Induced Liver Injury by Preventing Complement Overactivation. Cell Mol Gastroenterol Hepatol 2021; 13:289-307. [PMID: 34536564 PMCID: PMC8599171 DOI: 10.1016/j.jcmgh.2021.09.003] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 09/08/2021] [Accepted: 09/09/2021] [Indexed: 12/10/2022]
Abstract
BACKGROUND AND AIMS C-reactive protein (CRP) is a hepatocyte-produced marker of inflammation yet with undefined function in liver injury. We aimed to examine the role of CRP in acetaminophen-induced liver injury (AILI). METHODS The effects of CRP in AILI were investigated using CRP knockout mice and rats combined with human CRP rescue. The mechanisms of CRP action were investigated in vitro and in mice with Fcγ receptor 2B knockout, C3 knockout, or hepatic expression of CRP mutants defective in complement interaction. The therapeutic potential of CRP was investigated by intraperitoneal administration at 2 or 6 hours post-AILI induction in wild-type mice. RESULTS CRP knockout exacerbated AILI in mice and rats, which could be rescued by genetic knock-in, adeno-associated virus-mediated hepatic expression or direct administration of human CRP. Mechanistically, CRP does not act via its cellular receptor Fcγ receptor 2B to inhibit the early phase injury to hepatocytes induced by acetaminophen; instead, CRP acts via factor H to inhibit complement overactivation on already injured hepatocytes, thereby suppressing the late phase amplification of inflammation likely mediated by C3a-dependent actions of neutrophils. Importantly, CRP treatment effectively alleviated AILI with a significantly extended therapeutic time window than that of N-acetyl cysteine. CONCLUSION Our results thus identify CRP as a crucial checkpoint that limits destructive activation of complement in acute liver injury, and we argue that long-term suppression of CRP expression or function might increase the susceptibility to AILI.
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Affiliation(s)
- Hai-Yun Li
- MOE Key Laboratory of Environment and Genes Related to Diseases, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, P.R. China
| | - Zhao-Ming Tang
- MOE Key Laboratory of Environment and Genes Related to Diseases, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, P.R. China
| | - Zhe Wang
- MOE Key Laboratory of Environment and Genes Related to Diseases, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, P.R. China
| | - Jian-Min Lv
- MOE Key Laboratory of Environment and Genes Related to Diseases, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, P.R. China
| | - Xiao-Ling Liu
- MOE Key Laboratory of Cell Activities and Stress Adaptations, School of Life Sciences, Lanzhou University, Lanzhou, P.R. China
| | - Yu-Lin Liang
- MOE Key Laboratory of Cell Activities and Stress Adaptations, School of Life Sciences, Lanzhou University, Lanzhou, P.R. China
| | - Bin Cheng
- MOE Key Laboratory of Cell Activities and Stress Adaptations, School of Life Sciences, Lanzhou University, Lanzhou, P.R. China
| | - Ning Gao
- Department of Infectious Disease, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China
| | - Shang-Rong Ji
- MOE Key Laboratory of Cell Activities and Stress Adaptations, School of Life Sciences, Lanzhou University, Lanzhou, P.R. China,Shang-Rong Ji, PhD, MOE Key Laboratory of Cell Activities and Stress Adaptations, School of Life Sciences, Lanzhou University, Lanzhou 730000, P.R. China. fax: 86-931-8914102.
| | - Yi Wu
- MOE Key Laboratory of Environment and Genes Related to Diseases, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, P.R. China,Key Laboratory of Precision Medicine to Pediatric Diseases of Shaanxi Province, Xi’an Children’s Hospital, Xi'an Jiaotong University, Xi'an, P.R. China,Correspondence Address correspondence to: Yi Wu, PhD, MOE Key Laboratory of Environment and Genes Related to Diseases, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an 710061, P.R. China. fax: 86-029-82657013.
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49
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Kumar S, Duan Q, Wu R, Harris EN, Su Q. Pathophysiological communication between hepatocytes and non-parenchymal cells in liver injury from NAFLD to liver fibrosis. Adv Drug Deliv Rev 2021; 176:113869. [PMID: 34280515 PMCID: PMC11792083 DOI: 10.1016/j.addr.2021.113869] [Citation(s) in RCA: 180] [Impact Index Per Article: 45.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Revised: 06/16/2021] [Accepted: 07/11/2021] [Indexed: 02/07/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a multifactorial disease that encompasses a spectrum of pathological conditions, ranging from simple steatosis (NAFL), nonalcoholic steatohepatitis (NASH), fibrosis/cirrhosis which can further progress to hepatocellular carcinoma and liver failure. The progression of NAFL to NASH and liver fibrosis is closely associated with a series of liver injury resulting from lipotoxicity, oxidative stress, redox imbalance (excessive nitric oxide), ER stress, inflammation and apoptosis that occur sequentially in different liver cells which ultimately leads to the activation of liver regeneration and fibrogenesis, augmenting collagen and extracellular matrix deposition and promoting liver fibrosis and cirrhosis. Type 2 diabetes is a significant risk factor in NAFLD development by accelerating liver damage. Here, we overview recent findings from human study and animal models on the pathophysiological communication among hepatocytes (HCs), Kupffer cells (KCs), hepatic stellate cells (HSCs) and liver sinusoidal endothelial cells (LSECs) during the disease development. The mechanisms of crucial signaling pathways, including Toll-like receptor, TGFβ and hedgehog mediated hepatic injury are also discussed. We further highlight the potentials of precisely targeting hepatic individual cell-type using nanotechnology as therapeutic strategy for the treatment of NASH and liver fibrosis.
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Affiliation(s)
- Santosh Kumar
- Institute for Global Food Security, School of Biological Sciences, Queen's University Belfast, Belfast BT9 5DL, United Kingdom
| | - Qihua Duan
- Institute for Global Food Security, School of Biological Sciences, Queen's University Belfast, Belfast BT9 5DL, United Kingdom
| | - Rongxue Wu
- Department of Medicine, Section of Cardiology, University of Chicago, Chicago, USA
| | - Edward N Harris
- Department of Biochemistry, University of Nebraska-Lincoln, Lincoln, NE 68588, USA.
| | - Qiaozhu Su
- Institute for Global Food Security, School of Biological Sciences, Queen's University Belfast, Belfast BT9 5DL, United Kingdom.
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50
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Zhang Q, Li S, Cai L, Zhu Y, Duan X, Jiang P, Zhong L, Guo K, Tong R. Microenvironment Activatable Nanoprodrug Based on Gripper-like Cyclic Phenylboronic Acid to Precisely and Effectively Alleviate Drug-induced Hepatitis. Theranostics 2021; 11:8301-8321. [PMID: 34373743 PMCID: PMC8344015 DOI: 10.7150/thno.61214] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Accepted: 06/30/2021] [Indexed: 02/06/2023] Open
Abstract
Drug-induced hepatitis (DIH), which seriously interferes with disease treatment, is one of the most common reasons for termination of new drugs during preclinical studies or post-marketing surveillance. Although antioxidants and anti-inflammatory agents are promising, their nonspecific distribution and insolubility limit their application. Therefore, precise drug release at the disease site is an important way to alleviate DIH and avoid side effects. Methods: A gripper-like hydrophilic cyclic phenylboronic acid (cPBA) was synthesized and a nanoprodrug (cPBA-BE) was established by coupling cPBA with hydrophobic baicalein (BE). The stimuli-responsive release properties and therapeutic effect of cPBA-BE on drug-injured hepatocyte were investigated. The biodistribution and therapeutic effect of cPBA-BE both in acetaminophen-induced acute hepatitis model and rifampicin-induced chronic hepatitis model were further evaluated. Results: cPBA-BE conjugate could self-assemble into nanoprodrug with cPBA as the hydrophilic external layer and BE as the hydrophobic core. In HepaRG cells, cPBA-BE showed stronger cellular uptake. Due to the H2O2- and acid-sensitivity, cPBA-BE could achieve adequate BE release, significantly resist the depletion of GSH, mitochondrial dysfunction, downregulation of inflammation and cell apoptosis in the acetaminophen injured HepaRG cells. Biodistribution showed that cPBA-BE specifically increased the concentration of BE in the liver of DIH mice. cPBA-BE could alleviate acetaminophen-induced acute hepatitis or rifampicin-induced chronic hepatitis more effectively through relieving the oxidative stress, inflammation and block the neutrophil infiltration in liver. Conclusions: cPBA is expected to be a good platform for constructing injectable nanoprodrug with both H2O2 and pH-responsive properties by coupling a wide range of drugs containing o-diol. In this study, the nanoprodrug cPBA-BE was determined to be effective for alleviating the DIH.
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