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Liu MW, Duan SX, Zhao XY, Wang QF, Yang SL, Ma N, Li X. Research status and advances in dexmedetomidine for sepsis‑induced multiple organ dysfunction syndrome (Review). Int J Mol Med 2025; 55:94. [PMID: 40242975 PMCID: PMC12045470 DOI: 10.3892/ijmm.2025.5535] [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: 01/09/2025] [Accepted: 04/07/2025] [Indexed: 04/18/2025] Open
Abstract
Sepsis‑induced organ dysfunction syndrome (ODS) arises from a dysregulated response to infection, leading to multiple life‑threatening organ dysfunctions, and is a common complication in critically ill patients. Sepsis results in varying degrees of injury to the brain, lungs, kidneys and liver, culminating in immune dysfunction and multiple ODS (MODS). Current evidence indicates a direct correlation between the severity of organ injury and the prognosis of septic patients. Understanding the mechanisms of MODS in sepsis and developing effective management strategies are vital research areas. The protective effects of dexmedetomidine (DEX) on sepsis are well established, demonstrating its capacity to mitigate injuries to the brain, lungs, kidneys, liver and immune system. The present study reviews recent research progress on the role and mechanisms of action of DEX in the treatment of sepsis.
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Affiliation(s)
- Ming-Wei Liu
- Department of Emergency Medicine, Dali Bai Autonomous Prefecture People's Hospital, Dali, Yunnan 671000, P.R. China
| | - Shao-Xin Duan
- Department of Trauma, Dali Bai Autonomous Prefecture People's Hospital, Dali, Yunnan 671000, P.R. China
| | - Xue-Yan Zhao
- Department of Endocrinology, First Affiliated Hospital of Dali University, Dali, Yunnan 671000, P.R. China
| | - Qiong-Fen Wang
- Department of Gastroenterology, Dali Bai Autonomous Prefecture People's Hospital, Dali, Yunnan 671000, P.R. China
| | - Shan-Lan Yang
- Department of Oncology, Dali Bai Autonomous Prefecture People's Hospital, Dali, Yunnan 671000, P.R. China
| | - Ni Ma
- Department of Pharmacy, Dali Bai Autonomous Prefecture People's Hospital, Dali, Yunnan 671000, P.R. China
| | - Xuan Li
- Department of Rehabilitation, Dali Bai Autonomous Prefecture People's Hospital, Dali, Yunnan 671000, P.R. China
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Yang Y, Sun Z, Li J, Song Y, Xu W. Neutrophil-derived IL-10 increases CVB3-induced acute pancreatitis pathology via suppressing CD8 +T cell activation while increasing macrophage STAT3-IL-6 cascade. Cytokine 2024; 184:156784. [PMID: 39437614 DOI: 10.1016/j.cyto.2024.156784] [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: 08/13/2024] [Revised: 10/09/2024] [Accepted: 10/11/2024] [Indexed: 10/25/2024]
Abstract
Acute pancreatitis (AP) is a lethal inflammatory disease of the pancreas. Its pathogenesis remains obscure and specific treatments are lacking. An increase in Interleukin-10 (IL-10) in the early stage of AP patients is closely related to AP severity. In Coxsackievirus B3 (CVB3) induced murine AP model, we found early IL-10 increased viral replication and pancreatic inflammation, yet the cellular source of IL-10 and the immunomodulatory role of neutrophils during viral infection remains unknown. Here we show that CVB3 infection enhanced neutrophil infiltration and IL-10 expression in the pancreas at day3 post infection (p.i.). Neutrophils served as an important early source of pancreatic IL-10 at the initiation of infection. Day3 pancreas extracts (D3P) also induced bone-marrow derived neutrophils (BMneu) to secrete IL-10. Adoptive transfer of D3P-pretreated BMneu into IL-10 KO mice increased viral replication and pancreas histopathology, which effect was blunted by the absence of IL-10 in BMneu. Mechanically, IL-10+ neutrophil increased IL-10R1 expression on MΦs and activated STAT3-IL-6/IL-10 signaling cascade while decreased IL-12 and MHC II expression in MΦs, thus impairing IFN-γ+Granzyme B+CD8+T cell activation and viral clearance. Adoptive transferring infected mice with activated CD8+T cells 4 days p.i. attenuated viral load and AP pathology indicating an AP-protective effect. Our findings document a novel immunoregulatory function of neutrophils in acute CVB3 infection, in which neutrophil-derived IL-10 impairs anti-viral CD8+T activation, and amplifies intrapancreatic inflammation via activating MΦ STAT3-IL-6 signaling cascade. An IL-10-targeting option is suggested for the future treatment of viral AP.
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Affiliation(s)
- Yue Yang
- Institutes of Biology and Medical Sciences, Soochow University, Jiangsu Key Labotrary of Infection and Immunity, Suzhou 215123, China
| | - Zhirong Sun
- Institutes of Biology and Medical Sciences, Soochow University, Jiangsu Key Labotrary of Infection and Immunity, Suzhou 215123, China
| | - Jingrou Li
- Institutes of Biology and Medical Sciences, Soochow University, Jiangsu Key Labotrary of Infection and Immunity, Suzhou 215123, China
| | - Yahui Song
- Institutes of Biology and Medical Sciences, Soochow University, Jiangsu Key Labotrary of Infection and Immunity, Suzhou 215123, China
| | - Wei Xu
- Institutes of Biology and Medical Sciences, Soochow University, Jiangsu Key Labotrary of Infection and Immunity, Suzhou 215123, China.
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Wang D, Wang T, Kim D, Tan S, Liu S, Wan J, Deng Q. MicroRNA-375 modulates neutrophil chemotaxis via targeting Cathepsin B in zebrafish. FISH & SHELLFISH IMMUNOLOGY 2024; 154:109933. [PMID: 39343064 PMCID: PMC11561466 DOI: 10.1016/j.fsi.2024.109933] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Revised: 09/25/2024] [Accepted: 09/27/2024] [Indexed: 10/01/2024]
Abstract
Neutrophils are crucial for defense against numerous infections, and their migration and activations are tightly regulated to prevent collateral tissue damage. We previously performed a neutrophil-specific miRNA overexpression screening and identified several microRNAs, including miR-375, as potent modulators for neutrophil activity. Overexpression of miR-375 decreases neutrophil motility and migration in zebrafish and human neutrophil-like cells. We screened the genes downregulated by miR-375 in zebrafish neutrophils and identified that Cathepsin B (Ctsba) is required for neutrophil motility and chemotaxis upon tail wounding and bacterial infection. Pharmacological inhibition or neutrophil-specific knockout of ctsba significantly decreased the neutrophil chemotaxis in zebrafish and survival upon systemic bacterial infection. Notably, Ctsba knockdown in human neutrophil-like cells also resulted in reduced chemotaxis. Inhibiting integrin receptor function using RGDS rescued the neutrophil migration defects and susceptibility to systemic infection in zebrafish with either miR-375 overexpression or ctsba knockout. Our results demonstrate that miR-375 and its target Ctsba modulate neutrophil activity during tissue injury and bacterial infection in vivo, providing novel insights into neutrophil biology and the overall inflammation process.
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Affiliation(s)
- Decheng Wang
- Department of Biological Sciences, Purdue University, West Lafayette, IN, 47907, USA
| | - Tianqi Wang
- Department of Biological Sciences, Purdue University, West Lafayette, IN, 47907, USA
| | - Daniel Kim
- Department of Biological Sciences, Purdue University, West Lafayette, IN, 47907, USA
| | - Shelly Tan
- Department of Biological Sciences, Purdue University, West Lafayette, IN, 47907, USA
| | - Sheng Liu
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, 46202, USA; Collaborative Core for Cancer Bioinformatics, Indiana University Simon Cancer Center, Indianapolis, IN, 46202, USA
| | - Jun Wan
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, 46202, USA; Collaborative Core for Cancer Bioinformatics, Indiana University Simon Cancer Center, Indianapolis, IN, 46202, USA; Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
| | - Qing Deng
- Department of Biological Sciences, Purdue University, West Lafayette, IN, 47907, USA.
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Yang M, Chen T, Xu Y, Liu Q, Xu X. Study on the mechanism of Shenmai injection in the treatment of sepsis. J Cell Mol Med 2024; 28:e70201. [PMID: 39584444 PMCID: PMC11586680 DOI: 10.1111/jcmm.70201] [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: 08/05/2024] [Revised: 10/26/2024] [Accepted: 10/29/2024] [Indexed: 11/26/2024] Open
Abstract
Shenmai injection (SMI) is widely used in the clinical treatment of sepsis, but its mechanism is not yet clear. This study aimed to explore the molecular mechanism through network pharmacology, bioinformatics, and molecular docking technologies. The active ingredients and targets of SMI were screened through traditional Chinese medicine databases and the Swiss Target Prediction database, respectively. The disease genes were searched using GEO and GeneCards databases, and Venn mapping was used to screen potential therapeutic targets. The key targets were selected using Cytoscape 3.9.1 software. The BioGPS database was used to evaluate the expression of these targets in tissues/cells. The DAVID database is used for enrichment analysis. Molecular docking technology was used to evaluate the interaction between these targets and core active ingredients. 122 potential therapeutic targets and 28 key targets were identified. Forty-six potential therapeutic targets showed highly specific expression in 40 tissues/cells. The PI3K-AKT, RAP1, and MAPK signalling pathways are highly enriched. The molecular docking results showed good interactions. This study systematically analysed the mechanism of SMI in treating sepsis, involving multiple targets and pathways, possibly related to anti-inflammatory, anti-oxidative stress, and immune regulation, providing reference value for future basic research of sepsis.
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Affiliation(s)
- Mengxia Yang
- Beijing Hospital of Traditional Chinese MedicineCapital Medical UniversityBeijingChina
- Beijing institute of Traditional Chinese MedicineBeijingChina
- Graduate School of Beijing University of Chinese MedicineBeijingChina
| | - Tengfei Chen
- Beijing Hospital of Traditional Chinese MedicineCapital Medical UniversityBeijingChina
| | - Yue Xu
- China Science and Technology Development Center for Chinese MedicineBeijingChina
| | - Qingquan Liu
- Beijing Hospital of Traditional Chinese MedicineCapital Medical UniversityBeijingChina
- Beijing institute of Traditional Chinese MedicineBeijingChina
| | - Xiaolong Xu
- Beijing Hospital of Traditional Chinese MedicineCapital Medical UniversityBeijingChina
- Beijing institute of Traditional Chinese MedicineBeijingChina
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Cao Q, Li J, Chen M. Bioinformatics analysis of neutrophil-associated hub genes and ceRNA network construction in septic cardiomyopathy. Aging (Albany NY) 2024; 16:12833-12849. [PMID: 39216003 PMCID: PMC11501391 DOI: 10.18632/aging.206092] [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: 03/11/2024] [Accepted: 08/03/2024] [Indexed: 09/04/2024]
Abstract
Septic cardiomyopathy (SCM) is a critical sepsis complication characterized by reversible cardiac depression during early septic shock. Neutrophils, integral to innate immunity, can mediate organ damage when abnormal, but their specific role in sepsis-induced myocardial damage remains elusive. Our study focuses on elucidating the role of Neutrophil-Related Genes (NRGs) in SCM, finding early diagnosis and treatment biomarkers. We identified shared differentially expressed genes (DEGs) from datasets GSE79962 and GSE44363 and pinpointed hub DEGs using the cytoHubba plugin in Cytoscape software. The Neutrophil-Related Hub Gene (NRHG) MRC1 was identified via intersecting hub DEGs with NRGs from WGCNA. We validated MRC1's abnormal expression in SCM using our data and external datasets. Furthermore, a neutrophil-related ceRNA network (AC145207.5/ miR-23a-3p/MRC1) was constructed and validated. Our findings reveal MRC1 as a potential NRHG in SCM pathogenesis, offering insights into neutrophil-mediated mechanisms in SCM and providing a novel molecular target for early diagnosis and intervention in SCM.
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Affiliation(s)
- Qingfei Cao
- Department of Urology, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, China
| | - Jing Li
- Department of Pediatric, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, China
| | - Meixue Chen
- Department of Pediatric, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, China
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Shankar-Hari M, Calandra T, Soares MP, Bauer M, Wiersinga WJ, Prescott HC, Knight JC, Baillie KJ, Bos LDJ, Derde LPG, Finfer S, Hotchkiss RS, Marshall J, Openshaw PJM, Seymour CW, Venet F, Vincent JL, Le Tourneau C, Maitland-van der Zee AH, McInnes IB, van der Poll T. Reframing sepsis immunobiology for translation: towards informative subtyping and targeted immunomodulatory therapies. THE LANCET. RESPIRATORY MEDICINE 2024; 12:323-336. [PMID: 38408467 PMCID: PMC11025021 DOI: 10.1016/s2213-2600(23)00468-x] [Citation(s) in RCA: 38] [Impact Index Per Article: 38.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Revised: 11/27/2023] [Accepted: 12/07/2023] [Indexed: 02/28/2024]
Abstract
Sepsis is a common and deadly condition. Within the current model of sepsis immunobiology, the framing of dysregulated host immune responses into proinflammatory and immunosuppressive responses for the testing of novel treatments has not resulted in successful immunomodulatory therapies. Thus, the recent focus has been to parse observable heterogeneity into subtypes of sepsis to enable personalised immunomodulation. In this Personal View, we highlight that many fundamental immunological concepts such as resistance, disease tolerance, resilience, resolution, and repair are not incorporated into the current sepsis immunobiology model. The focus for addressing heterogeneity in sepsis should be broadened beyond subtyping to encompass the identification of deterministic molecular networks or dominant mechanisms. We explicitly reframe the dysregulated host immune responses in sepsis as altered homoeostasis with pathological disruption of immune-driven resistance, disease tolerance, resilience, and resolution mechanisms. Our proposal highlights opportunities to identify novel treatment targets and could enable successful immunomodulation in the future.
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Affiliation(s)
- Manu Shankar-Hari
- Institute for Regeneration and Repair, College of Medicine and Veterinary Medicine, The University of Edinburgh, Edinburgh, UK.
| | - Thierry Calandra
- Service of Immunology and Allergy, Center of Human Immunology Lausanne, Department of Medicine and Department of Laboratory Medicine and Pathology, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland
| | | | - Michael Bauer
- Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany
| | - W Joost Wiersinga
- Center for Experimental and Molecular Medicine and Division of Infectious Diseases, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, Netherlands
| | - Hallie C Prescott
- Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Julian C Knight
- Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - Kenneth J Baillie
- Institute for Regeneration and Repair, College of Medicine and Veterinary Medicine, The University of Edinburgh, Edinburgh, UK
| | - Lieuwe D J Bos
- Department of Intensive Care, Academic Medical Center, Amsterdam, Netherlands
| | - Lennie P G Derde
- Intensive Care Center, University Medical Center Utrecht, Utrecht, Netherlands
| | - Simon Finfer
- Critical Care Division, The George Institute for Global Health, University of New South Wales, Sydney, NSW, Australia
| | - Richard S Hotchkiss
- Department of Anesthesiology and Critical Care Medicine, Washington University School of Medicine in St Louis, St Louis, MO, USA
| | - John Marshall
- Interdepartmental Division of Critical Care, University of Toronto, Toronto, ON, Canada
| | | | - Christopher W Seymour
- Department of Critical Care Medicine, The Clinical Research, Investigation, and Systems Modeling of Acute illness (CRISMA) Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Fabienne Venet
- Immunology Laboratory, Edouard Herriot Hospital, Hospices Civils de Lyon, Lyon, France
| | | | - Christophe Le Tourneau
- Department of Drug Development and Innovation (D3i), Institut Curie, Paris-Saclay University, Paris, France
| | - Anke H Maitland-van der Zee
- Department of Pulmonary Medicine, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, Netherlands
| | - Iain B McInnes
- College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
| | - Tom van der Poll
- Center for Experimental and Molecular Medicine and Division of Infectious Diseases, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, Netherlands
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Dou Y, Li W, Nan Y, Zhang Y, Peng S. Feature augmentation and semi-supervised conditional transfer learning for early detection of sepsis. Comput Biol Med 2023; 165:107418. [PMID: 37716243 DOI: 10.1016/j.compbiomed.2023.107418] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Revised: 07/25/2023] [Accepted: 08/28/2023] [Indexed: 09/18/2023]
Abstract
Early detection of Sepsis is crucial for improving patient outcomes, as it is a significant public health concern that results in substantial morbidity and mortality. However, despite the widespread use of the Sequential Organ Failure Assessment (SOFA) in clinical settings to identify sepsis, obtaining sufficient physiological data before onset remains challenging, limiting early detection of sepsis. To address this challenge, we propose an interpretable machine learning model, ITFG (Interpretable Tree-based Feature Generation), that leverages potential correlations between features based on existing knowledge to identify sepsis within six hours of onset using valuable and continuous physiological measures. Furthermore, we introduce a Semi-supervised Attention-based Conditional Transfer Learning (SAC-TL) framework to enhance the model's generality and enable it to be used for early warning of sepsis in the target domain with less information from the source domain. Our proposed approaches effectively address the problem of systematic feature sparsity and missing data, while also being practical for different degrees of generalizability. We evaluated our proposed approaches on open datasets, MIMIC and PhysioNet, obtaining AUC of 97.98% and 86.21%, respectively, demonstrating their effectiveness in different data environments and achieving the best early detection results.
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Affiliation(s)
- Yutao Dou
- College of Computer Science and Electronic Engineering, Hunan University, Changsha, 410082, China; Centre for Distributed and High Performance Computing, School of Computer Science, The University of Sydney, Darlington, NSW, 2008, Australia.
| | - Wei Li
- Centre for Distributed and High Performance Computing, School of Computer Science, The University of Sydney, Darlington, NSW, 2008, Australia
| | - Yucen Nan
- Centre for Distributed and High Performance Computing, School of Computer Science, The University of Sydney, Darlington, NSW, 2008, Australia
| | - Yidi Zhang
- State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Beijing, China
| | - Shaoliang Peng
- College of Computer Science and Electronic Engineering, Hunan University, Changsha, 410082, China.
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Maus KD, Stephenson DJ, Macknight HP, Vu NT, Hoeferlin LA, Kim M, Diegelmann RF, Xie X, Chalfant CE. Skewing cPLA 2α activity toward oxoeicosanoid production promotes neutrophil N2 polarization, wound healing, and the response to sepsis. Sci Signal 2023; 16:eadd6527. [PMID: 37433004 PMCID: PMC10565596 DOI: 10.1126/scisignal.add6527] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Accepted: 06/16/2023] [Indexed: 07/13/2023]
Abstract
Uncontrolled inflammation is linked to poor outcomes in sepsis and wound healing, both of which proceed through distinct inflammatory and resolution phases. Eicosanoids are a class of bioactive lipids that recruit neutrophils and other innate immune cells. The interaction of ceramide 1-phosphate (C1P) with the eicosanoid biosynthetic enzyme cytosolic phospholipase A2 (cPLA2) reduces the production of a subtype of eicosanoids called oxoeicosanoids. We investigated the effect of shifting the balance in eicosanoid biosynthesis on neutrophil polarization and function. Knockin mice expressing a cPLA2 mutant lacking the C1P binding site (cPLA2αKI/KI mice) showed enhanced and sustained neutrophil infiltration into wounds and the peritoneum during the inflammatory phase of wound healing and sepsis, respectively. The mice exhibited improved wound healing and reduced susceptibility to sepsis, which was associated with an increase in anti-inflammatory N2-type neutrophils demonstrating proresolution behaviors and a decrease in proinflammatory N1-type neutrophils. The N2 polarization of cPLA2αKI/KI neutrophils resulted from increased oxoeicosanoid biosynthesis and autocrine signaling through the oxoeicosanoid receptor OXER1 and partially depended on OXER1-dependent inhibition of the pentose phosphate pathway (PPP). Thus, C1P binding to cPLA2α suppresses neutrophil N2 polarization, thereby impairing wound healing and the response to sepsis.
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Affiliation(s)
- Kenneth D Maus
- Department of Cell Biology, Microbiology, and Molecular Biology, University of South Florida, Tampa, FL 33620, USA
| | - Daniel J Stephenson
- Department of Medicine, Division of Hematology and Oncology, University of Virginia, Charlottesville, VA 22903, USA
| | - H Patrick Macknight
- Department of Medicine, Division of Hematology and Oncology, University of Virginia, Charlottesville, VA 22903, USA
| | - Ngoc T Vu
- Department of Applied Biochemistry, School of Biotechnology, International University-VNU HCM, Ho Chi Minh City, Vietnam
| | - L Alexis Hoeferlin
- Department of Biochemistry and Molecular Biology, Virginia Commonwealth University-School of Medicine, Richmond VA 23298, USA
| | - Minjung Kim
- Department of Cell Biology, Microbiology, and Molecular Biology, University of South Florida, Tampa, FL 33620, USA
| | - Robert F Diegelmann
- Department of Biochemistry and Molecular Biology, Virginia Commonwealth University-School of Medicine, Richmond VA 23298, USA
| | - Xiujie Xie
- Department of Medicine, Division of Hematology and Oncology, University of Virginia, Charlottesville, VA 22903, USA
| | - Charles E Chalfant
- Department of Medicine, Division of Hematology and Oncology, University of Virginia, Charlottesville, VA 22903, USA
- Department of Cell Biology, University of Virginia, Charlottesville, VA 22903, USA
- Program in Cancer Biology, University of Virginia Cancer Center, Charlottesville, VA 22903, USA
- Research Service, Richmond Veterans Administration Medical Center, Richmond VA, 23298, USA
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Shu Q, She H, Chen X, Zhong L, Zhu J, Fang L. Identification and experimental validation of mitochondria-related genes biomarkers associated with immune infiltration for sepsis. Front Immunol 2023; 14:1184126. [PMID: 37228596 PMCID: PMC10203506 DOI: 10.3389/fimmu.2023.1184126] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2023] [Accepted: 04/26/2023] [Indexed: 05/27/2023] Open
Abstract
Background Sepsis remains a complex condition with incomplete understanding of its pathogenesis. Further research is needed to identify prognostic factors, risk stratification tools, and effective diagnostic and therapeutic targets. Methods Three GEO datasets (GSE54514, GSE65682, and GSE95233) were used to explore the potential role of mitochondria-related genes (MiRGs) in sepsis. WGCNA and two machine learning algorithms (RF and LASSO) were used to identify the feature of MiRGs. Consensus clustering was subsequently carried out to determine the molecular subtypes for sepsis. CIBERSORT algorithm was conducted to assess the immune cell infiltration of samples. A nomogram was also established to evaluate the diagnostic ability of feature biomarkers via "rms" package. Results Three different expressed MiRGs (DE-MiRGs) were identified as sepsis biomarkers. A significant difference in the immune microenvironment landscape was observed between healthy controls and sepsis patients. Among the DE-MiRGs, NDUFB3 was selected to be a potential therapeutic target and its significant elevated expression level was confirmed in sepsis using in vitro experiments and confocal microscopy, indicating its significant contribution to the mitochondrial quality imbalance in the LPS-simulated sepsis model. Conclusion By digging the role of these pivotal genes in immune cell infiltration, we gained a better understanding of the molecular immune mechanism in sepsis and identified potential intervention and treatment strategies.
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Affiliation(s)
- Qi Shu
- Zhejiang Cancer Hospital, Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
| | - Han She
- Department of Anesthesiology, Daping Hospital, Army Medical University, Chongqing, China
| | - Xi Chen
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Like Zhong
- Zhejiang Cancer Hospital, Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
| | - Junfeng Zhu
- Zhejiang Cancer Hospital, Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
| | - Luo Fang
- Zhejiang Cancer Hospital, Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
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10
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Hu P, Lu YH, Deng W, Li Q, Zhao N, Shao Q, Wu L, Wang XZ, Qian KJ, Liu F. The critical role of pancreatic stone protein/regenerating protein in sepsis-related multiorgan failure. Front Med (Lausanne) 2023; 10:1172529. [PMID: 37215716 PMCID: PMC10196489 DOI: 10.3389/fmed.2023.1172529] [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: 02/23/2023] [Accepted: 04/13/2023] [Indexed: 05/24/2023] Open
Abstract
Introduction Multiple organ dysfunction syndrome (MODS) is common in patients with sepsistic admitted to an intensive care unit (ICU) and greatly increases mortality. Pancreatic stone protein/regenerating protein (PSP/Reg) is a type of C-type lectin protein that is overexpressed during sepsis. This study aimed to evaluate the potential involvement of PSP/Reg in MODS development in patients with sepsis. Materials and methods The relationship between circulating PSP/Reg levels, patient prognosis, and progression to MODS was analyzed in patients with sepsis admitted to the ICU of a general tertiary hospital. Furthermore, to examine the potential involvement of PSP/Reg in sepsis-induced MODS, a septic mouse model was established per the cecal ligation and puncture procedure, randomized into three groups, and subjected to a caudal vein injection of recombinant PSP/Reg at two different doses and phosphate-buffered saline. Survival analyses and disease severity scoring were performed to evaluate the survival status of the mice; enzyme-linked immunosorbent assays were performed to detect the levels of inflammatory factors and organ-damage markers in murine peripheral blood; terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining was performed to measure apoptosis levels in lung, heart, liver, and kidney tissue sections and to visualize the degree of organ damage in the mouse model; myeloperoxidase activity assay, immunofluorescence staining, and flow cytometry were performed to detect neutrophil infiltration levels in vital murine organs and the activation indexes of neutrophils. Results and discussion Our findings indicated that Circulating PSP/Reg levels were correlated with patient prognosis and sequential organ failure assessment scores. Furthermore, PSP/Reg administration increased disease severity scores, shortened survival time, increased the TUNEL-positive staining rate, and increased the levels of inflammatory factors, organ-damage markers, and neutrophil infiltration in the organs. Neutrophils can be activated by PSP/Reg to an inflammatory state, both in vivo and in vitro, which is characterized by the increased levels of intercellular adhesion molecule 1 and CD29. Conclusion Patient prognosis and progression to MODS can be visualized by monitoring PSP/Reg levels upon ICU admission. Additionally, PSP/Reg administration in animal models exacerbates the inflammatory response and severity of multiorgan damage, which may be accomplished by promoting the inflammatory state of neutrophils.
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Affiliation(s)
- Ping Hu
- Department of Critical Care Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
- Medical Innovation Center, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Yuan hua Lu
- Department of Critical Care Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Wei Deng
- Department of Critical Care Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
- Medical Innovation Center, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Qi Li
- Department of Critical Care Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Ning Zhao
- Department of Critical Care Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Qiang Shao
- Department of Critical Care Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Ling Wu
- Department of Critical Care Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Xu zhen Wang
- Department of Critical Care Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
- Medical Innovation Center, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Ke jian Qian
- Department of Critical Care Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Fen Liu
- Department of Critical Care Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
- Medical Innovation Center, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
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Li Y, Tan R, Li R, Tian R, Liu Z, Wang X, Chen E, Pan T, Qu H. PKM2/STAT1-mediated PD-L1 upregulation on neutrophils during sepsis promotes neutrophil organ accumulation by serving an anti-apoptotic role. J Inflamm (Lond) 2023; 20:16. [PMID: 37131151 PMCID: PMC10155438 DOI: 10.1186/s12950-023-00341-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Accepted: 04/25/2023] [Indexed: 05/04/2023] Open
Abstract
BACKGROUND Delayed neutrophil apoptosis during sepsis may impact neutrophil organ accumulation and tissue immune homeostasis. Elucidating the mechanisms underlying neutrophil apoptosis may help identify potential therapeutic targets. Glycolysis is critical to neutrophil activities during sepsis. However, the precise mechanisms through which glycolysis regulates neutrophil physiology remain under-explored, especially those involving the non-metabolic functions of glycolytic enzymes. In the present study, the impact of programmed death ligand-1 (PD-L1) on neutrophil apoptosis was explored. The regulatory effect of the glycolytic enzyme, pyruvate kinase M2 (PKM2), whose role in septic neutrophils remains unaddressed, on neutrophil PD-L1 expression was also explored. METHODS Peripheral blood neutrophils were isolated from patients with sepsis and healthy controls. PD-L1 and PKM2 levels were determined by flow cytometry and Western blotting, respectively. Dimethyl sulfoxide (DMSO)-differentiated HL-60 cells were stimulated with lipopolysaccharide (LPS) as an in vitro simulation of septic neutrophils. Cell apoptosis was assessed by annexin V/propidium iodide (annexin V/PI) staining, as well as determination of protein levels of cleaved caspase-3 and myeloid cell leukemia-1 (Mcl-1) by Western blotting. An in vivo model of sepsis was constructed by intraperitoneal injection of LPS (5 mg/kg) for 16 h. Pulmonary and hepatic neutrophil infiltration was assessed by flow cytometry or immunohistochemistry. RESULTS PD-L1 level was elevated on neutrophils under septic conditions. Administration of neutralizing antibodies against PD-L1 partially reversed the inhibitory effect of LPS on neutrophil apoptosis. Neutrophil infiltration into the lung and liver was also reduced in PD-L1-/- mice 16 h after sepsis induction. PKM2 was upregulated in septic neutrophils and promoted neutrophil PD-L1 expression both in vitro and in vivo. In addition, PKM2 nuclear translocation was increased after LPS stimulation, which promoted PD-L1 expression by directly interacting with and activating signal transducer and activator of transcription 1 (STAT1). Inhibition of PKM2 activity or STAT1 activation also led to increased neutrophil apoptosis. CONCLUSION In this study, a PKM2/STAT1-mediated upregulation of PD-L1 on neutrophils and the anti-apoptotic effect of upregulated PD-L1 on neutrophils during sepsis were identified, which may result in increased pulmonary and hepatic neutrophil accumulation. These findings suggest that PKM2 and PD-L1 could serve as potential therapeutic targets.
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Affiliation(s)
- Yinjiaozhi Li
- Department of Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin Er Road, Shanghai, 200025, China
| | - Ruoming Tan
- Department of Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin Er Road, Shanghai, 200025, China
| | - Ranran Li
- Department of Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin Er Road, Shanghai, 200025, China
| | - Rui Tian
- Department of Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin Er Road, Shanghai, 200025, China
| | - Zhaojun Liu
- Department of Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin Er Road, Shanghai, 200025, China
| | - Xiaoli Wang
- Department of Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin Er Road, Shanghai, 200025, China
| | - Erzhen Chen
- Department of Emergency Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin Er Road, Shanghai, 200025, China
| | - Tingting Pan
- Department of Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin Er Road, Shanghai, 200025, China.
| | - Hongping Qu
- Department of Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin Er Road, Shanghai, 200025, China.
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Zanza C, Caputo G, Tornatore G, Romenskaya T, Piccioni A, Franceschi F, Artico M, Taurone S, Savioli G, Longhitano Y. Cellular Immuno-Profile in Septic Human Host: A Scoping Review. BIOLOGY 2022; 11:1626. [PMID: 36358327 PMCID: PMC9687154 DOI: 10.3390/biology11111626] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Revised: 11/01/2022] [Accepted: 11/02/2022] [Indexed: 11/09/2022]
Abstract
Innate and adaptive immune system cells play a critical role in the host response to sepsis. Sepsis is a life-threatening disease characterized by apoptosis-induced depletion of immune cells and immunodepression, which contribute to morbidity and mortality. Many alterations in the expression of surface markers of neutrophils and monocytes have been described in septic patients. The aim of this study was to inspect the recently published literature to inform the clinician about the most up-to-date techniques for the study of circulating leukocytes. The impact on cell phenotypes and on the function of leukocytes of extracorporeal and non-blood purification treatments proposed for sepsis were also analyzed. We conducted a systematic review using Pubmed/Medline, Ovid/Willey, the Cochrane Library, the Cochrane Controlled Trials Register, and EMBASE, combining key terms related to immunological function in sepsis and selected the most relevant clinical trials and review articles (excluding case reports) published in the last 50 years. The most important alteration in neutrophils during sepsis is that they activate an anti-apoptotic survival program. In septic monocytes, a reduced characteristic expression of HLA-DR is observed, but their role does not seem to be significantly altered in sepsis. As regards adaptive immunity, sepsis leads to lymphopenia and immunosuppression in patients with septic shock; this process involves all types of T cells (CD4, CD8 and Natural Killer), except for regulatory T cells, which retain their function. Several promising therapies that target the host immune response are currently under evaluation. During the worldwide pandemic caused by SARS-CoV-2, it was useful to study the "cytokine storm" to find additional treatments, such as the oXiris® filter. This therapy can decrease the concentration of inflammatory markers that affect the severity of the disease.
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Affiliation(s)
- Christian Zanza
- Foundation “Ospedale Alba e Bra”, Department of Emergency Medicine, Anesthesia and Critical Care Medicine, Michele and Pietro Ferrero Hospital, 12060 Verduno, Italy
- Department of Emergency Medicine, Policlinico Gemelli-RCCS-Catholic University of Sacred Heart, 00168 Rome, Italy
- Department of Anesthesia and Critical Care Medicine, St. Antonio and Biagio Hospital, 15121 Alessandria, Italy
| | - Giorgia Caputo
- Department of Anesthesia and Critical Care Medicine, St. Antonio and Biagio Hospital, 15121 Alessandria, Italy
| | - Gilda Tornatore
- Department of Anesthesia and Intensive Care Medicine, University of Milan-Bicocca, 20126 Milan, Italy
| | - Tatsiana Romenskaya
- Department of Anesthesia and Critical Care Medicine, St. Antonio and Biagio Hospital, 15121 Alessandria, Italy
| | - Andrea Piccioni
- Department of Emergency Medicine, Policlinico Gemelli-RCCS-Catholic University of Sacred Heart, 00168 Rome, Italy
| | - Francesco Franceschi
- Department of Emergency Medicine, Policlinico Gemelli-RCCS-Catholic University of Sacred Heart, 00168 Rome, Italy
| | - Marco Artico
- Department of Sensory Organs, Policlinico Umberto I, Sapienza University of Rome, 00185 Rome, Italy
| | - Samanta Taurone
- Department of Movement, Human and Health Sciences—Division of Health Sciences, University of Rome “Foro Italico”, 00135 Rome, Italy
| | - Gabriele Savioli
- Department of Emergency Medicine, Polyclinic IRCCS S. Matteo, University of Pavia, 27100 Pavia, Italy
| | - Yaroslava Longhitano
- Foundation “Ospedale Alba e Bra”, Department of Emergency Medicine, Anesthesia and Critical Care Medicine, Michele and Pietro Ferrero Hospital, 12060 Verduno, Italy
- Department of Anesthesia and Critical Care Medicine, St. Antonio and Biagio Hospital, 15121 Alessandria, Italy
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13
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Juncos LA, Wieruszewski PM, Kashani K. Pathophysiology of Acute Kidney Injury in Critical Illness: A Narrative Review. Compr Physiol 2022; 12:3767-3780. [PMID: 36073750 DOI: 10.1002/cphy.c210028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Acute kidney injury (AKI) is a syndrome that entails a rapid decline in kidney function with or without injury. The consequences of AKI among acutely ill patients are dire and lead to higher mortality, morbidity, and healthcare cost. To prevent AKI and its short and long-term repercussions, understanding its pathophysiology is essential. Depending on the baseline kidney histology and function reserves, the number of kidney insults, and the intensity of each insult, the clinical presentation of AKI may differ. While many factors are capable of inducing renal injury, they can be categorized into a few processes. The three primary processes reported in the literature are hemodynamic changes, inflammatory reactions, and nephrotoxicity. The majority of patients with AKI will suffer from more than one during their development and/or progression of AKI. Moreover, the development of one usually leads to the instigation of another. Thus, the interactions and progression between these mechanisms may determine the severity and duration of the AKI. Other factors such as organ crosstalk and how our concurrent therapies interact with these mechanisms complicate the pathophysiology of the progression of the AKI even further. In this narrative review article, we describe these three main pathophysiological processes that lead to the development and progression of AKI. © 2022 American Physiological Society. Compr Physiol 12: 1-14, 2022.
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Affiliation(s)
- Luis A Juncos
- Division of Nephrology, Central Arkansas Veterans' Healthcare System, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
| | - Patrick M Wieruszewski
- Division of Hospital Pharmacy, Department of Pharmacy, Mayo Clinic, Rochester, Minnesota, USA
| | - Kianoush Kashani
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA.,Division of Pulmonary and Critical Care Medicine, Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA
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14
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Fu Y, Xiang Y, Li H, Chen A, Dong Z. Inflammation in kidney repair: Mechanism and therapeutic potential. Pharmacol Ther 2022; 237:108240. [PMID: 35803367 DOI: 10.1016/j.pharmthera.2022.108240] [Citation(s) in RCA: 60] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Revised: 06/29/2022] [Accepted: 06/30/2022] [Indexed: 02/07/2023]
Abstract
The kidney has a remarkable ability of repair after acute kidney injury (AKI). However, when injury is severe or persistent, the repair is incomplete or maladaptive and may lead to chronic kidney disease (CKD). Maladaptive kidney repair involves multiple cell types and multifactorial processes, of which inflammation is a key component. In the process of inflammation, there is a bidirectional interplay between kidney parenchymal cells and the immune system. The extensive and complex crosstalk between renal tubular epithelial cells and interstitial cells, including immune cells, fibroblasts, and endothelial cells, governs the repair and recovery of the injured kidney. Further research in this field is imperative for the discovery of biomarkers and promising therapeutic targets for kidney repair. In this review, we summarize the latest progress in the immune response and inflammation during maladaptive kidney repair, analyzing the interaction between immune cells and intrinsic kidney cells, pointing out the potentialities of inflammation-related pathways as therapeutic targets, and discussing the challenges and future research prospects in this field.
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Affiliation(s)
- Ying Fu
- Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital at Central South University, Changsha 410011, China
| | - Yu Xiang
- Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital at Central South University, Changsha 410011, China
| | - Honglin Li
- Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital at Central South University, Changsha 410011, China
| | - Anqun Chen
- Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital at Central South University, Changsha 410011, China
| | - Zheng Dong
- Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital at Central South University, Changsha 410011, China; Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University and Charlie Norwood VA Medical Center, Augusta, GA, USA.
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15
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The Impact of Cytokines on Neutrophils' Phagocytosis and NET Formation during Sepsis-A Review. Int J Mol Sci 2022; 23:ijms23095076. [PMID: 35563475 PMCID: PMC9101385 DOI: 10.3390/ijms23095076] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Revised: 04/29/2022] [Accepted: 04/30/2022] [Indexed: 02/04/2023] Open
Abstract
Sepsis is an overwhelming inflammatory response to infection, resulting in multiple-organ injury. Neutrophils are crucial immune cells involved in innate response to pathogens and their migration and effector functions, such as phagocytosis and neutrophil extracellular trap (NET) formation, are dependent on cytokine presence and their concentration. In the course of sepsis, recruitment and migration of neutrophils to infectious foci gradually becomes impaired, thus leading to loss of a crucial arm of the innate immune response to infection. Our review briefly describes the sepsis course, the importance of neutrophils during sepsis, and explains dependence between cytokines and their activation. Moreover, we, for the first time, summarize the impact of cytokines on phagocytosis and NET formation. We highlight and discuss the importance of cytokines in modulation of both processes and emphasize the direction of further investigations.
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16
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Lartey NL, Vargas-Robles H, Guerrero-Fonseca IM, García-Ponce A, Salinas-Lara C, Rottner K, Schnoor M. The Actin-Binding Protein Cortactin Promotes Sepsis Severity by Supporting Excessive Neutrophil Infiltration into the Lung. Biomedicines 2022; 10:biomedicines10051019. [PMID: 35625756 PMCID: PMC9139066 DOI: 10.3390/biomedicines10051019] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Revised: 04/11/2022] [Accepted: 04/14/2022] [Indexed: 12/12/2022] Open
Abstract
Sepsis is a systemic infection that can lead to multi-organ failure. It is characterised by an uncontrolled immune response with massive neutrophil influx into peripheral organs. Neutrophil extravasation into tissues depends on actin remodeling and actin-binding proteins such as cortactin, which is expressed ubiquitously, except for neutrophils. Endothelial cortactin is necessary for proper regulation of neutrophil transendothelial migration and recruitment to sites of infection. We therefore hypothesised that cortactin plays a crucial role in sepsis development by regulating neutrophil trafficking. Using a murine model of sepsis induced by cecal ligation and puncture (CLP), we showed that cortactin-deficient (KO) mice survive better due to reduced lung injury. Histopathological analysis of lungs from septic KO mice revealed absence of oedema, reduced vascular congestion and mucus deposition, and better-preserved alveoli compared to septic wild-type (WT) mice. Additionally, sepsis-induced cytokine storm, excessive neutrophil infiltration into the lung and oxidative stress were significantly reduced in KO mice. Neutrophil depletion 12 h after sepsis improved survival in WT mice by averting lung injury, similar to both neutrophil-depleted and non-depleted KO mice. Our findings highlight a critical role of cortactin for lung neutrophil infiltration and sepsis severity.
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Affiliation(s)
- Nathaniel L. Lartey
- Department of Molecular Biomedicine, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV-IPN), Mexico City 07360, Mexico; (N.L.L.); (H.V.-R.); (I.M.G.-F.); (A.G.-P.)
| | - Hilda Vargas-Robles
- Department of Molecular Biomedicine, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV-IPN), Mexico City 07360, Mexico; (N.L.L.); (H.V.-R.); (I.M.G.-F.); (A.G.-P.)
| | - Idaira M. Guerrero-Fonseca
- Department of Molecular Biomedicine, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV-IPN), Mexico City 07360, Mexico; (N.L.L.); (H.V.-R.); (I.M.G.-F.); (A.G.-P.)
| | - Alexander García-Ponce
- Department of Molecular Biomedicine, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV-IPN), Mexico City 07360, Mexico; (N.L.L.); (H.V.-R.); (I.M.G.-F.); (A.G.-P.)
| | | | - Klemens Rottner
- Division of Molecular Cell Biology, Zoological Institute, Technical University Braunschweig, 38106 Braunschweig, Germany;
- Helmholtz Centre for Infection Research, Department of Cell Biology, 38124 Braunschweig, Germany
| | - Michael Schnoor
- Department of Molecular Biomedicine, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV-IPN), Mexico City 07360, Mexico; (N.L.L.); (H.V.-R.); (I.M.G.-F.); (A.G.-P.)
- Correspondence: ; Tel.: +52-55-5747-3321
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17
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HS1 deficiency protects against sepsis by attenuating neutrophil-inflicted lung damage. Eur J Cell Biol 2022; 101:151214. [PMID: 35286924 PMCID: PMC10170315 DOI: 10.1016/j.ejcb.2022.151214] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 03/02/2022] [Accepted: 03/07/2022] [Indexed: 12/20/2022] Open
Abstract
Sepsis remains an important health problem worldwide due to inefficient treatments often resulting in multi-organ failure. Neutrophil recruitment is critical during sepsis. While neutrophils are required to combat invading bacteria, excessive neutrophil recruitment contributes to tissue damage due to their arsenal of molecular weapons that do not distinguish between host and pathogen. Thus, neutrophil recruitment needs to be fine-tuned to ensure bacterial killing, while avoiding neutrophil-inflicted tissue damage. We recently showed that the actin-binding protein HS1 promotes neutrophil extravasation; and hypothesized that HS1 is also a critical regulator of sepsis progression. We evaluated the role of HS1 in a model of lethal sepsis induced by cecal-ligation and puncture. We found that septic HS1-deficient mice had a better survival rate compared to WT mice due to absence of lung damage. Lungs of septic HS1-deficient mice showed less inflammation, fibrosis, and vascular congestion. Importantly, systemic CLP-induced neutrophil recruitment was attenuated in the lungs, the peritoneum and the cremaster in the absence of HS1. Lungs of HS1-deficient mice produced significantly more interleukin-10. Compared to WT neutrophils, those HS1-deficient neutrophils that reached the lungs had increased surface levels of Gr-1, ICAM-1, and L-selectin. Interestingly, HS1-deficient neutrophils had similar F-actin content and phagocytic activity, but they failed to polymerize actin and deform in response to CXCL-1 likely explaining the reduced systemic neutrophil recruitment in HS1-deficient mice. Our data show that HS1 deficiency protects against sepsis by attenuating neutrophil recruitment to amounts sufficient to combat bacterial infection, but insufficient to induce tissue damage.
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18
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Yang S, Ouyang J, Lu Y, Harypursat V, Chen Y. A Dual Role of Heme Oxygenase-1 in Tuberculosis. Front Immunol 2022; 13:842858. [PMID: 35281042 PMCID: PMC8913507 DOI: 10.3389/fimmu.2022.842858] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Accepted: 02/08/2022] [Indexed: 12/19/2022] Open
Abstract
Iron metabolism is vital for the survival of both humans and microorganisms. Heme oxygenase-1 (HO-1) is an essential stress-response enzyme highly expressed in the lungs, and catabolizes heme into ferrous iron, carbon monoxide (CO), and biliverdin (BV)/bilirubin (BR), especially in pathological conditions which cause oxidative stress and inflammation. Ferrous iron (Fe2+) is an important raw material for the synthesis of hemoglobin in red blood cells, and patients with iron deficiency are often associated with decreased cellular immunity. CO and BR can inhibit oxidative stress and inflammation. Thus, HO-1 is regarded as a cytoprotective molecule during the infection process. However, recent study has unveiled new information regarding HO-1. Being a highly infectious pathogenic bacterium, Mycobacterium tuberculosis (MTB) infection causes acute oxidative stress, and increases the expression of HO-1, which may in turn facilitate MTB survival and growth due to increased iron availability. Moreover, in severe cases of MTB infection, excessive reactive oxygen species (ROS) and free iron (Fe2+) due to high levels of HO-1 can lead to lipid peroxidation and ferroptosis, which may promote further MTB dissemination from cells undergoing ferroptosis. Therefore, it is important to understand and illustrate the dual role of HO-1 in tuberculosis. Herein, we critically review the interplay among HO-1, tuberculosis, and the host, thus paving the way for development of potential strategies for modulating HO-1 and iron metabolism.
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19
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Thornton JM, Yin K. Role of Specialized Pro-Resolving Mediators in Modifying Host Defense and Decreasing Bacterial Virulence. Molecules 2021; 26:molecules26226970. [PMID: 34834062 PMCID: PMC8618792 DOI: 10.3390/molecules26226970] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Revised: 11/05/2021] [Accepted: 11/15/2021] [Indexed: 12/12/2022] Open
Abstract
Bacterial infection activates the innate immune system as part of the host’s defense against invading pathogens. Host response to bacterial pathogens includes leukocyte activation, inflammatory mediator release, phagocytosis, and killing of bacteria. An appropriate host response requires resolution. The resolution phase involves attenuation of neutrophil migration, neutrophil apoptosis, macrophage recruitment, increased phagocytosis, efferocytosis of apoptotic neutrophils, and tissue repair. Specialized Pro-resolving Mediators (SPMs) are bioactive fatty acids that were shown to be highly effective in promoting resolution of infectious inflammation and survival in several models of infection. In this review, we provide insight into the role of SPMs in active host defense mechanisms for bacterial clearance including a new mechanism of action in which an SPM acts directly to reduce bacterial virulence.
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Haute GV, Luft C, Pedrazza L, Donadio MVF, de Oliveira JR. Octyl gallate decrease lymphocyte activation and regulates neutrophil extracellular traps release. Mol Biol Rep 2021; 49:1593-1599. [PMID: 34783987 DOI: 10.1007/s11033-021-06937-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Accepted: 11/05/2021] [Indexed: 11/26/2022]
Abstract
BACKGROUND Inflammation is a complex mechanism with an objective to destroy and eliminate the invading microorganisms. During acute inflammation, the neutrophils are the major cells involved in this process and, although they defend the organism, must die to not generate damage. The two major mechanisms that drive neutrophils to death are: apoptosis and a novel mechanism recently discovered denominated NETosis. This process is a "suicidal mechanism", in which the cells release "neutrophil extracellular traps" (NETs) during the inflammatory response. Octyl gallate (OG) is one of the gallic acid derivates, with several protective effects, such as antioxidant and anti-inflammatory in cancer models. Thus, this study aimed to investigate the action of OG on the proliferation of lymphocytes, neutrophils activation, and its effectiveness in an experimental sepsis model. METHODS Lymphocytes and neutrophils were obtained from healthy donors. Cell viability, apoptosis, NETs release and antioxidant capacity of OG were observed. In addition, survival was evaluated in an experimental model of sepsis in C57BL/6 mice. RESULTS Our study demonstrated, for the first time, that the OG can act as an inhibitor of reactive oxygen species (ROS) release, NETs formation in primary human neutrophils and, modulates the lipopolysaccharide (LPS) effect in neutrophil apoptosis. The OG also inhibited peripheral blood mononuclear cells (PBMCs) proliferation in vitro. Despite the positive results, we did not observe an increase in the survival of septic animals. CONCLUSIONS The pharmacological potential of OG, modulating activation of neutrophils and lymphocytes, suggests the use as an adjuvant therapeutic strategy in inflammatory diseases.
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Affiliation(s)
- Gabriela Viegas Haute
- Laboratório de Pesquisa em Biofísica Celular e Inflamação, Departamento de Biologia Celular e Molecular, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Avenida Ipiranga 6681, prédio 12, bloco C, sala 221, Porto Alegre, CEP 90619-900, Brazil
| | - Carolina Luft
- Laboratório de Pesquisa em Biofísica Celular e Inflamação, Departamento de Biologia Celular e Molecular, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Avenida Ipiranga 6681, prédio 12, bloco C, sala 221, Porto Alegre, CEP 90619-900, Brazil
- Laboratório de Respirologia Pediátrica, Instituto de Pesquisas Biomédicas (IPB), Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, RS, Brazil
| | - Leonardo Pedrazza
- Laboratório de Pesquisa em Biofísica Celular e Inflamação, Departamento de Biologia Celular e Molecular, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Avenida Ipiranga 6681, prédio 12, bloco C, sala 221, Porto Alegre, CEP 90619-900, Brazil.
| | - Márcio Vinícius Fagundes Donadio
- Laboratório de Pesquisa em Biofísica Celular e Inflamação, Departamento de Biologia Celular e Molecular, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Avenida Ipiranga 6681, prédio 12, bloco C, sala 221, Porto Alegre, CEP 90619-900, Brazil
- Laboratório de Respirologia Pediátrica, Instituto de Pesquisas Biomédicas (IPB), Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, RS, Brazil
| | - Jarbas Rodrigues de Oliveira
- Laboratório de Pesquisa em Biofísica Celular e Inflamação, Departamento de Biologia Celular e Molecular, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Avenida Ipiranga 6681, prédio 12, bloco C, sala 221, Porto Alegre, CEP 90619-900, Brazil.
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Yao W, Xu L, Jia X, Li S, Wei L. MicroRNA‑129 plays a protective role in sepsis‑induced acute lung injury through the suppression of pulmonary inflammation via the modulation of the TAK1/NF‑κB pathway. Int J Mol Med 2021; 48:139. [PMID: 34080641 PMCID: PMC8175065 DOI: 10.3892/ijmm.2021.4972] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2020] [Accepted: 05/07/2021] [Indexed: 12/18/2022] Open
Abstract
Excessive inflammatory response and apoptosis play key roles in the pathogenic mechanisms of sepsis-induced acute lung injury (ALI); however, the molecular pathways linked to ALI pathogenesis remain unclear. Recently, microRNAs (miRNAs/miRs) have emerged as important regulators of inflammation and apoptosis in sepsis-induced ALI; however, the exact regulatory mechanisms of miRNAs remain poorly understood. In the present study, the gene microarray dataset GSE133733 obtained from the Gene Expression Omnibus database was analyzed and a total of 38 differentially regulated miRNAs were identified, including 17 upregulated miRNAs and 21 downregulated miRNAs, in mice with lipopolysaccharide (LPS)-induced ALI, in comparison to the normal control mice. miR-129 was found to be the most significant miRNA, among the identified miRNAs. The upregulation of miR-129 markedly alleviated LPS-induced lung injury, as indicated by the decrease in lung permeability in and the wet-to-dry lung weight ratio, as well as the improved survival rate of mice with ALI administered miR-129 mimic. Moreover, the upregulation of miR-129 reduced pulmonary inflammation and apoptosis in mice with ALI. Of note, transforming growth factor activated kinase-1 (TAK1), a well-known regulator of the nuclear factor-κB (NF-κB) pathway, was directly targeted by miR-129 in RAW 264.7 cells. More importantly, miR-129 upregulation impeded the LPS-induced activation of the TAK1/NF-κB signaling pathway, as illustrated by the suppression of the nuclear phosphorylated-p65, p-IκB-α and p-IKKβ expression levels. Collectively, the findings of the present study indicate that miR-129 protects mice against sepsis-induced ALI by suppressing pulmonary inflammation and apoptosis through the regulation of the TAK1/NF-κB signaling pathway. This introduces the basis for future research concerning the application of miR-129 and its targets for the treatment of ALI.
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Affiliation(s)
- Wenjian Yao
- Department of Thoracic Surgery, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, School of Clinical Medicine, Henan University, Zhengzhou, Henan 450003, P.R. China
| | - Lei Xu
- Department of Thoracic Surgery, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, School of Clinical Medicine, Henan University, Zhengzhou, Henan 450003, P.R. China
| | - Xiangbo Jia
- Department of Thoracic Surgery, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, School of Clinical Medicine, Henan University, Zhengzhou, Henan 450003, P.R. China
| | - Saisai Li
- Department of Thoracic Surgery, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, School of Clinical Medicine, Henan University, Zhengzhou, Henan 450003, P.R. China
| | - Li Wei
- Department of Thoracic Surgery, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, School of Clinical Medicine, Henan University, Zhengzhou, Henan 450003, P.R. China
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22
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Bailey WP, Cui K, Ardell CL, Keever KR, Singh S, Rodriguez-Gil DJ, Ozment TR, Williams DL, Yakubenko VP. Frontline Science: The expression of integrin α D β 2 (CD11d/CD18) on neutrophils orchestrates the defense mechanism against endotoxemia and sepsis. J Leukoc Biol 2021; 109:877-890. [PMID: 33438263 PMCID: PMC8085079 DOI: 10.1002/jlb.3hi0820-529rr] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Revised: 12/07/2020] [Accepted: 12/08/2020] [Indexed: 12/14/2022] Open
Abstract
Neutrophil-macrophage interplay is a fine-tuning mechanism that regulates the innate immune response during infection and inflammation. Cell surface receptors play an essential role in neutrophil and macrophage functions. The same receptor can provide different outcomes within diverse leukocyte subsets in different inflammatory conditions. Understanding the variety of responses mediated by one receptor is critical for the development of anti-inflammatory treatments. In this study, we evaluated the role of a leukocyte adhesive receptor, integrin αD β2 , in the development of acute inflammation. αD β2 is mostly expressed on macrophages and contributes to the development of chronic inflammation. In contrast, we found that αD -knockout dramatically increases mortality in the cecal ligation and puncture sepsis model and LPS-induced endotoxemia. This pathologic outcome of αD -deficient mice is associated with a reduced number of monocyte-derived macrophages and an increased number of neutrophils in their lungs. However, the tracking of adoptively transferred fluorescently labeled wild-type (WT) and αD-/- monocytes in WT mice during endotoxemia demonstrated only a moderate difference between the recruitment of these two subsets. Moreover, the rescue experiment, using i.v. injection of WT monocytes to αD -deficient mice followed by LPS challenge, showed only slightly reduced mortality. Surprisingly, the injection of WT neutrophils to the bloodstream of αD-/- mice markedly increased migration of monocyte-derived macrophage to lungs and dramatically improves survival. αD -deficient neutrophils demonstrate increased necrosis/pyroptosis. αD β2 -mediated macrophage accumulation in the lungs promotes efferocytosis that reduced mortality. Hence, integrin αD β2 implements a complex defense mechanism during endotoxemia, which is mediated by macrophages via a neutrophil-dependent pathway.
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Affiliation(s)
- William P Bailey
- Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee, USA
| | - Kui Cui
- Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee, USA
| | - Christopher L Ardell
- Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee, USA
| | - Kasey R Keever
- Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee, USA
| | - Sanjay Singh
- Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee, USA
| | - Diego J Rodriguez-Gil
- Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee, USA
| | - Tammy R Ozment
- Department of Surgery, Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee, USA
- Center of Excellence in Inflammation, Infectious Disease and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee, USA
| | - David L Williams
- Department of Surgery, Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee, USA
- Center of Excellence in Inflammation, Infectious Disease and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee, USA
| | - Valentin P Yakubenko
- Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee, USA
- Center of Excellence in Inflammation, Infectious Disease and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee, USA
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23
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Abstract
ABSTRACT Neutrophils play a critical role in the eradication of pathogenic organisms, particularly bacteria. However, in the septic patient the prolonged activation and accumulation of neutrophils may augment tissue and organ injury. This review discusses the different activation states and chemotaxis of neutrophils in septic patients. Neutrophil killing of bacteria and the formation of neutrophil extracellular traps represent important components of the innate immune response and they become dysregulated during sepsis, possibly through changes in their metabolism. Delayed neutrophil apoptosis may contribute to organ injury, or allow better clearance of pathogens. Neutrophils provide a friendly immune response to clear infections, but excessive activation and recruitment has the potential to turn them into potent foes.
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24
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Zhang Y, Lin R, Pradhan K, Geng S, Li L. Innate Priming of Neutrophils Potentiates Systemic Multiorgan Injury. Immunohorizons 2020; 4:392-401. [PMID: 32631901 PMCID: PMC7445012 DOI: 10.4049/immunohorizons.2000039] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Accepted: 06/14/2020] [Indexed: 11/19/2022] Open
Abstract
Excessive inflammatory reactions mediated by first-responder cells such as neutrophils contribute to the severity of multiorgan failure associated with systemic injury and infection. Systemic subclinical endotoxemia due to mucosal leakage may aggravate neutrophil activation and tissue injury. However, mechanisms responsible for neutrophil inflammatory polarization are not well understood. In this study, we demonstrate that subclinical low-dose endotoxemia can potently polarize neutrophils into an inflammatory state in vivo and in vitro, as reflected in elevated expression of adhesion molecules such as ICAM-1 and CD29, and reduced expression of suppressor molecule CD244. When subjected to a controlled administration of gut-damaging chemical dextran sulfate sodium, mice conditioned with subclinical dose LPS exhibit significantly elevated infiltration of neutrophils into organs such as liver, colon, and spleen, associated with severe multiorgan damage as measured by biochemical as well as histological assays. Subclinical dose LPS is sufficient to induce potent activation of SRC kinase as well as downstream activation of STAT1/STAT5 in neutrophils, contributing to the inflammatory neutrophil polarization. We also demonstrate that the administration of 4-phenylbutyric acid, an agent known to relieve cell stress and enhance peroxisome function, can reduce the activation of SRC kinase and enhance the expression of suppressor molecule CD244 in neutrophils. We show that i.v. injection of 4-phenylbutyric acid conditioned neutrophils can effectively reduce the severity of multiorgan damage in mice challenged with dextran sulfate sodium. Collectively, our data, to our knowledge, reveal novel inflammatory polarization of neutrophils by subclinical endotoxemia conducive for aggravated multiorgan damage as well as potential therapeutic intervention.
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Affiliation(s)
- Yao Zhang
- Department of Biological Sciences, Virginia Tech, Blacksburg, VA 24061; and
| | - RuiCi Lin
- Translational Biology, Medicine, and Health Graduate Program, Virginia Tech, Blacksburg, VA 24061
| | - Kisha Pradhan
- Department of Biological Sciences, Virginia Tech, Blacksburg, VA 24061; and
| | - Shuo Geng
- Department of Biological Sciences, Virginia Tech, Blacksburg, VA 24061; and
| | - Liwu Li
- Department of Biological Sciences, Virginia Tech, Blacksburg, VA 24061; and
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25
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Fattahi F, Grailer JJ, Parlett M, Lu H, Malan EA, Abe E, Russell MW, Frydrych LM, Delano MJ, Zetoune FS, Ward PA. Requirement of Complement C6 for Intact Innate Immune Responses in Mice. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2020; 205:251-260. [PMID: 32444389 DOI: 10.4049/jimmunol.1900801] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/12/2019] [Accepted: 04/01/2020] [Indexed: 12/11/2022]
Abstract
Over the first days of polymicrobial sepsis, there is robust activation of the innate immune system, causing the appearance of proinflammatory cytokines and chemokines, along with the appearance of extracellular histones, which are highly proinflammatory and prothrombotic. In the current study, we studied different innate immune responses in mice with knockout (KO) of complement protein 6 (C6). Polymorphonuclear neutrophils (PMNs) from these KO mice had defective innate immune responses, including defective expression of surface adhesion molecules, generation of superoxide anion, and appearance of reactive oxygen species and histone release after activation of PMNs, along with defective phagocytosis. In addition, in C6-/- mice, the NLRP3 inflammasome was defective both in PMNs and in macrophages. When these KO mice were subjected to polymicrobial sepsis, their survival was improved, associated with reduced levels in the plasma of proinflammatory cytokines and chemokines and lower levels of histones in plasma. In addition, sepsis-induced cardiac dysfunction was attenuated in these KO mice. In a model of acute lung injury induced by LPS, C6-/- mice showed reduced PMN buildup and less lung epithelial/endothelial cell dysfunction (edema and hemorrhage). These data indicate that C6-/- mice have reduced innate immune responses that result in less organ injury and improved survival after polymicrobial sepsis.
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Affiliation(s)
- Fatemeh Fattahi
- Division of Allergy and Clinical Immunology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109
- Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109
| | - Jamison J Grailer
- Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109
| | - Michella Parlett
- Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109
| | - Hope Lu
- Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109
| | - Elizabeth A Malan
- Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109
| | - Elizabeth Abe
- Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109
| | - Mark W Russell
- Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, MI 48109; and
| | - Lynn M Frydrych
- Department of Surgery, University of Michigan School Medical School, Ann Arbor, MI 48109
| | - Matthew J Delano
- Department of Surgery, University of Michigan School Medical School, Ann Arbor, MI 48109
| | - Firas S Zetoune
- Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109
| | - Peter A Ward
- Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109;
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26
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Cheng Z, Abrams ST, Toh J, Wang SS, Downey C, Ge X, Yu Q, Yu W, Wang G, Toh CH. Complexes between C-Reactive Protein and Very Low Density Lipoprotein Delay Bacterial Clearance in Sepsis. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2020; 204:2712-2721. [PMID: 32269097 DOI: 10.4049/jimmunol.1900962] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/12/2019] [Accepted: 02/19/2020] [Indexed: 11/19/2022]
Abstract
C-reactive protein (CRP) can increase up to 1000-fold in blood and form complexes with very low density lipoproteins (VLDL). These complexes are associated with worse outcomes for septic patients, and this suggests a potential pathological role in sepsis. Complex formation is heightened when CRP is over 200 mg/l and levels are associated with the severity of sepsis and blood bacterial culture positivity. Using a mouse bacteremia model, blood bacterial clearance can be delayed by i.v. injection of CRP-VLDL complexes. Complexes are more efficiently taken up by activated U937 cells in vitro and Kupffer cells in vivo than VLDL alone. Both in vitro-generated and naturally occurring CRP-VLDL complexes reduce phagocytosis of bacteria by activated U937 cells. Fcγ and scavenger receptors are involved and a competitive mechanism for clearance of CRP-VLDL complexes and bacteria is demonstrated. Interaction of phosphocholine groups on VLDL with CRP is the major driver for complex formation and phosphocholine can disrupt the complexes to reverse their inhibitory effects on phagocytosis and bacterial clearance. Increased formation of CRP-VLDL complexes is therefore harmful and could be a novel target for therapy in sepsis.
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Affiliation(s)
- Zhenxing Cheng
- Medical School, Southeast University, Nanjing 210009, China
| | - Simon T Abrams
- Institute of Infection and Global Health, University of Liverpool, Liverpool L69 7BE, United Kingdom
| | - Julien Toh
- Wirral University Teaching Hospital NHS Foundation Trust, Upton, Wirral CH49 5PE, United Kingdom
| | - Susan S Wang
- Royal London Hospital, Whitechapel, London E1 1FR, United Kingdom; and
| | - Colin Downey
- Royal Liverpool University Hospital, University of Liverpool, Liverpool L7 8XP, United Kingdom
| | - Xiaoling Ge
- Institute of Infection and Global Health, University of Liverpool, Liverpool L69 7BE, United Kingdom
| | - Qian Yu
- Medical School, Southeast University, Nanjing 210009, China
| | - Weiping Yu
- Medical School, Southeast University, Nanjing 210009, China
| | - Guozheng Wang
- Medical School, Southeast University, Nanjing 210009, China;
- Institute of Infection and Global Health, University of Liverpool, Liverpool L69 7BE, United Kingdom
| | - Cheng-Hock Toh
- Institute of Infection and Global Health, University of Liverpool, Liverpool L69 7BE, United Kingdom
- Royal Liverpool University Hospital, University of Liverpool, Liverpool L7 8XP, United Kingdom
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27
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Abstract
There is abundant evidence that infectious sepsis both in humans and mice with polymicrobial sepsis results in robust activation of complement. Major complement activation products involved in sepsis include C5a anaphylatoxin and its receptors (C5aR1 and C5aR2) and, perhaps, the terminal complement activation product, C5b-9. These products (and others) also cause dysfunction of the innate immune system, with exaggerated early proinflammatory responses, followed by decline of the innate immune system, leading to immunosuppression and multiorgan dysfunction. Generation of C5a during sepsis also leads to activation of neutrophils and macrophages and ultimate appearance of extracellular histones, which have powerful proinflammatory and prothrombotic activities. The distal complement activation product, C5b-9, triggers intracellular Ca fluxes in epithelial and endothelial cells. Histones activate the NLRP3 inflammasome, products of which can damage cells. C5a also activates MAPKs and Akt signaling pathways in cardiomyocytes, causing buildup of [Ca]i, defective action potentials and substantial cell dysfunction, resulting in cardiac and other organ dysfunction. Cardiac dysfunction can be quantitated by ECHO-Doppler parameters. In vivo interventions that block these complement-dependent products responsible for organ dysfunction in sepsis reduce the intensity of sepsis. The obvious targets in sepsis are C5a and its receptors, histones, and perhaps the MAPK pathways. Blockade of C5 has been considered in sepsis, but the FDA-approved antibody (eculizumab) is known to compromise defenses against neisseria and pneumonococcal bacteria, and requires immunization before the mAb to C5 can be used clinically. Small molecular blocking agents for C5aRs are currently in development and may be therapeutically effective for treatment of sepsis.
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28
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Mesenchymal stromal cell-based therapies for acute kidney injury: progress in the last decade. Kidney Int 2020; 97:1130-1140. [PMID: 32305128 DOI: 10.1016/j.kint.2019.12.019] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2019] [Revised: 12/21/2019] [Accepted: 12/23/2019] [Indexed: 12/17/2022]
Abstract
A little over 10 years ago, the therapeutic potential of mesenchymal stromal cells (MSCs) for the treatment of acute kidney injury (AKI) was becoming widely recognized. Since then, there has been further intensive study of this topic with a clear translational intent. Over the past decade, many more animal model studies have strengthened the evidence that systemically or locally delivered MSCs ameliorate renal injury in sterile and sepsis-associated AKI. Some of these preclinical studies have also provided a range of compelling new insights into the in vivo fate and mechanisms of action of MSCs in the setting of AKI and other inflammatory conditions. Coupled with increased knowledge of the functional roles of resident and infiltrating immune cell mediators in determining the severity and outcome of AKI, the progress made in the past decade would appear to have significantly strengthened the translational pathway for MSC-based therapies. In contrast, however, the extent of the clinical experience with MSC administration in human subjects with AKI or sepsis-associated AKI has been limited to a small number of early-phase clinical trials, which appear to demonstrate safety but have not thus far delivered a strong signal of efficacy. In this review, we summarize the most significant new developments in the field of MSC-based therapies as they relate to AKI and reflect on the key gaps in knowledge and technology that remain to be addressed for the true clinical potential of MSCs and, perhaps, other emerging cellular therapies to be realized.
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29
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Andrade-Oliveira V, Foresto-Neto O, Watanabe IKM, Zatz R, Câmara NOS. Inflammation in Renal Diseases: New and Old Players. Front Pharmacol 2019; 10:1192. [PMID: 31649546 PMCID: PMC6792167 DOI: 10.3389/fphar.2019.01192] [Citation(s) in RCA: 227] [Impact Index Per Article: 37.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2019] [Accepted: 09/17/2019] [Indexed: 12/11/2022] Open
Abstract
Inflammation, a process intimately linked to renal disease, can be defined as a complex network of interactions between renal parenchymal cells and resident immune cells, such as macrophages and dendritic cells, coupled with recruitment of circulating monocytes, lymphocytes, and neutrophils. Once stimulated, these cells activate specialized structures such as Toll-like receptor and Nod-like receptor (NLR). By detecting danger-associated molecules, these receptors can set in motion major innate immunity pathways such as nuclear factor ĸB (NF-ĸB) and NLRP3 inflammasome, causing metabolic reprogramming and phenotype changes of immune and parenchymal cells and triggering the secretion of a number of inflammatory mediators that can cause irreversible tissue damage and functional loss. Growing evidence suggests that this response can be deeply impacted by the crosstalk between the kidneys and other organs, such as the gut. Changes in the composition and/or metabolite production of the gut microbiota can influence inflammation, oxidative stress, and fibrosis, thus offering opportunities to positively manipulate the composition and/or functionality of gut microbiota and, consequentially, ameliorate deleterious consequences of renal diseases. In this review, we summarize the most recent evidence that renal inflammation can be ameliorated by interfering with the gut microbiota through the administration of probiotics, prebiotics, and postbiotics. In addition to these innovative approaches, we address the recent discovery of new targets for drugs long in use in clinical practice. Angiotensin II receptor antagonists, NF-ĸB inhibitors, thiazide diuretics, and antimetabolic drugs can reduce renal macrophage infiltration and slow down the progression of renal disease by mechanisms independent of those usually attributed to these compounds. Allopurinol, an inhibitor of uric acid production, has been shown to decrease renal inflammation by limiting activation of the NLRP3 inflammasome. So far, these protective effects have been shown in experimental studies only. Clinical studies will establish whether these novel strategies can be incorporated into the arsenal of treatments intended to prevent the progression of human disease.
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Affiliation(s)
- Vinicius Andrade-Oliveira
- Bernardo's Lab, Center for Natural and Human Sciences, Federal University of ABC, Santo André, Brazil.,Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Orestes Foresto-Neto
- Renal Division, Department of Clinical Medicine, Faculty of Medicine, University of São Paulo, São Paulo, Brazil
| | - Ingrid Kazue Mizuno Watanabe
- Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.,Nephrology Division, Federal University of São Paulo, São Paulo, Brazil
| | - Roberto Zatz
- Renal Division, Department of Clinical Medicine, Faculty of Medicine, University of São Paulo, São Paulo, Brazil
| | - Niels Olsen Saraiva Câmara
- Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.,Renal Division, Department of Clinical Medicine, Faculty of Medicine, University of São Paulo, São Paulo, Brazil.,Nephrology Division, Federal University of São Paulo, São Paulo, Brazil
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30
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Abstract
Sepsis is a major health problem all over the world. Despite its existence since the time of Hippocrates (470 BC), sepsis is still a serious medical problem for physicians working in both pediatric and adult intensive care units. The most current US FDA-approved drug called recombinant human activated protein C or Drotrecogin-α is also failed in clinical trials and showed similar effects as placebo. The epidemiological data and studies have indicated sepsis as a major socioeconomic burden all over the world. Advances in immunology and genomic medicine have established different immunological mechanisms as major regulators of the pathogenesis of the sepsis. These immunological mechanisms come into action upon activation of several components of the immune system including innate and adaptive immunity. The activation of these immune cells in response to the pathogens or pathogen-associated molecular patterns (PAMPs) responsible for the onset of sepsis is regulated by the metabolic stage of the immune cells called immunometabolism. An alternation in the immunometabolism is responsible for the generation of dysregulated immune response during sepsis and plays a very important role in the process. Thus, it becomes vital to understand the immunometabolic reprograming during sepsis to design future target-based therapeutics depending on the severity. The current review is designed to highlight the importance of immune response and associated immunometabolism during sepsis and its targeting as a future therapeutic approach.
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Affiliation(s)
- Vijay Kumar
- Children's Health Queensland Clinical Unit, Department of Paediatrics and Child Care, School of Clinical Medicine, Mater Research, Faculty of Medicine, University of Queensland, ST Lucia, Brisbane, QLD, 4078, Australia.
- School of Biomedical Sciences, Faculty of Medicine, University of Queensland, ST Lucia, Brisbane, QLD, 4078, Australia.
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31
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Abstract
In addition to their well-known role as the cellular mediators of immunity, key other roles have been identified for neutrophils during septic shock. Importantly, neutrophils indeed play a critical role in the recently described immunothrombosis concept and in septic shock-induced coagulopathy. Septic shock is one of the most severe forms of infection, characterized by an inadequate host response to the pathogenic organism. This host response involves numerous defense mechanisms with an intense cellular activation, including neutrophil activation. Neutrophils are key cells of innate immunity through complex interactions with vascular cells and their activation may participate in systemic tissue damages. Their activation also leads to the emission of neutrophil extracellular traps, which take part in both pathogen circumscription and phagocytosis, but also in coagulation activation. Neutrophils thus stand at the interface between hemostasis and immunity, called immunothrombosis.The present review will develop a cellular approach of septic shock pathophysiology focusing on neutrophils as key players of septic shock-induced vascular cell dysfunction and of the host response, associating immunity and hemostasis. We will therefore first develop the role of neutrophils in the interplay between innate and adaptive immunity, and will then highlight recent advances in our understanding of immunothrombosis septic shock-induced coagulopathy.
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32
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Sheats MK. A Comparative Review of Equine SIRS, Sepsis, and Neutrophils. Front Vet Sci 2019; 6:69. [PMID: 30931316 PMCID: PMC6424004 DOI: 10.3389/fvets.2019.00069] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2018] [Accepted: 02/15/2019] [Indexed: 12/15/2022] Open
Abstract
The most recent definition of sepsis in human medicine can be summarized as organ dysfunction caused by a dysregulated host response to infection. In equine medicine, although no consensus definition is available, sepsis is commonly described as a dysregulated host systemic inflammatory response to infection. Defense against host infection is the primary role of innate immune cells known as neutrophils. Neutrophils also contribute to host injury during sepsis, making them important potential targets for sepsis prevention, diagnosis, and treatment. This review will present both historical and updated perspectives on the systemic inflammatory response (SIRS) and sepsis; it will also discuss the impact of sepsis on neutrophils, and the impact of neutrophils during sepsis. Future identification of clinically relevant sepsis diagnosis and therapy depends on a more thorough understanding of disease pathogenesis across species. To gain this understanding, there is a critical need for research that utilizes a clearly defined, and consistently applied, classification system for patients diagnosed with, and at risk of developing, sepsis.
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Affiliation(s)
- M. Katie Sheats
- Department of Clinical Sciences, North Carolina State University College of Veterinary Medicine, Raleigh, NC, United States
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33
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Piliponsky AM, Shubin NJ, Lahiri AK, Truong P, Clauson M, Niino K, Tsuha AL, Nedospasov SA, Karasuyama H, Reber LL, Tsai M, Mukai K, Galli SJ. Basophil-derived tumor necrosis factor can enhance survival in a sepsis model in mice. Nat Immunol 2019; 20:129-140. [PMID: 30664762 PMCID: PMC6352314 DOI: 10.1038/s41590-018-0288-7] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2017] [Accepted: 11/20/2018] [Indexed: 11/11/2022]
Abstract
Basophils are evolutionarily conserved in vertebrates, despite their small numbers and short lifespan, suggesting that basophils have beneficial roles in maintaining health. However, these roles are not fully defined. Here, we demonstrate that basophil-deficient mice exhibited reduced bacterial clearance, and increased morbidity and mortality, in the cecal ligation and puncture (CLP) model of sepsis. Among the several pro-inflammatory mediators we measured, tumor necrosis factor (TNF) was the only cytokine that was significantly reduced in basophil-deficient mice after CLP. In accordance with that observation, we found that mice with genetic ablation of Tnf in basophils exhibited reduced systemic TNF concentrations during endotoxemia. Moreover, during CLP, mice whose basophils could not produce TNF exhibited reduced neutrophil and macrophage TNF production and effector functions, reduced bacterial clearance, and increased mortality. Taken together, our studies show that basophils can enhance the innate immune response against bacterial infection and help prevent sepsis.
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Affiliation(s)
- Adrian M Piliponsky
- Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, WA, USA. .,Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, USA. .,Department of Pathology, University of Washington School of Medicine, Seattle, WA, USA.
| | - Nicholas J Shubin
- Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, WA, USA
| | - Asha K Lahiri
- Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, WA, USA
| | - Phuong Truong
- Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, WA, USA
| | - Morgan Clauson
- Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, WA, USA
| | - Kerri Niino
- Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, WA, USA
| | - Avery L Tsuha
- Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, WA, USA
| | - Sergei A Nedospasov
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia
| | - Hajime Karasuyama
- Tokyo Medical and Dental University Graduate School of Medical and Dental Sciences, Tokyo, Japan
| | - Laurent L Reber
- Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA
| | - Mindy Tsai
- Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.,Sean N. Parker Center for Allergy and Asthma Research, Stanford University School of Medicine, Stanford, CA, USA
| | - Kaori Mukai
- Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.,Sean N. Parker Center for Allergy and Asthma Research, Stanford University School of Medicine, Stanford, CA, USA
| | - Stephen J Galli
- Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.,Sean N. Parker Center for Allergy and Asthma Research, Stanford University School of Medicine, Stanford, CA, USA.,Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA
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34
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E. coli induced larger neutrophils in the peritoneal cavity of mice with severe septic peritonitis. Mol Immunol 2018; 105:86-95. [PMID: 30500625 DOI: 10.1016/j.molimm.2018.11.010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2018] [Revised: 10/23/2018] [Accepted: 11/14/2018] [Indexed: 12/26/2022]
Abstract
Neutrophils, classified as professional phagocytes, are crucial in killing bacteria and preventing inflammation. When studying the roles of neutrophils in the development of the septic peritonitis induced by E. coli, we noticed some of the larger cells existed among peritoneal lavage fluid cells (PLCs). Besides the large size, their nuclei are segmented and flat, and squeezed to the marginal zone of the inner membrane. The cells, therefore, were designated as E. coli induced larger neutrophils (e-Neus). Further studies showed that, the e-Neus were ly6G positive, indicating the e-Neus were a type of neutrophils. The enlarged cell size and marginal nucleus of the e-Neus were caused by engulfing abundant of E. coli, marking the active participation of the e-Neus in clearance of E. coli. Functionally, the e-Neus generated reactive oxygen species (ROS) and IL-10. Furthermore, the occurrence and accumulation of the e-Neus were closely correlated with the severity of septic peritonitis and mortality of the mice. Overall, the e-Neus presented here may enrich the understandings on neutrophil transitions in response to various insults, and could be used to evaluate the severity of septic peritonitis induced by E. coli.
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Omega-9 Oleic Acid, the Main Compound of Olive Oil, Mitigates Inflammation during Experimental Sepsis. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2018; 2018:6053492. [PMID: 30538802 PMCID: PMC6260523 DOI: 10.1155/2018/6053492] [Citation(s) in RCA: 64] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/06/2018] [Revised: 09/26/2018] [Accepted: 10/10/2018] [Indexed: 12/21/2022]
Abstract
The Mediterranean diet, rich in olive oil, is beneficial, reducing the risk of cardiovascular diseases and cancer. Olive oil is mostly composed of the monounsaturated fatty acid omega-9. We showed omega-9 protects septic mice modulating lipid metabolism. Sepsis is initiated by the host response to infection with organ damage, increased plasma free fatty acids, high levels of cortisol, massive cytokine production, leukocyte activation, and endothelial dysfunction. We aimed to analyze the effect of omega-9 supplementation on corticosteroid unbalance, inflammation, bacterial elimination, and peroxisome proliferator-activated receptor (PPAR) gamma expression, an omega-9 receptor and inflammatory modulator. We treated mice for 14 days with omega-9 and induced sepsis by cecal ligation and puncture (CLP). We measured systemic corticosterone levels, cytokine production, leukocyte and bacterial counts in the peritoneum, and the expression of PPAR gamma in both liver and adipose tissues during experimental sepsis. We further studied omega-9 effects on leukocyte rolling in mouse cremaster muscle-inflamed postcapillary venules and in the cerebral microcirculation of septic mice. Here, we demonstrate that omega-9 treatment is associated with increased levels of the anti-inflammatory cytokine IL-10 and decreased levels of the proinflammatory cytokines TNF-α and IL-1β in peritoneal lavage fluid of mice with sepsis. Omega-9 treatment also decreased systemic corticosterone levels. Neutrophil migration from circulation to the peritoneal cavity and leukocyte rolling on the endothelium were decreased by omega-9 treatment. Omega-9 also decreased bacterial load in the peritoneal lavage and restored liver and adipose tissue PPAR gamma expression in septic animals. Our data suggest a beneficial anti-inflammatory role of omega-9 in sepsis, mitigating leukocyte rolling and leukocyte influx, balancing cytokine production, and controlling bacterial growth possibly through a PPAR gamma expression-dependent mechanism. The significant reduction of inflammation detected after omega-9 enteral injection can further contribute to the already known beneficial properties facilitated by unsaturated fatty acid-enriched diets.
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Low-power laser alters mRNA levels from DNA repair genes in acute lung injury induced by sepsis in Wistar rats. Lasers Med Sci 2018; 34:157-168. [DOI: 10.1007/s10103-018-2656-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2018] [Accepted: 09/30/2018] [Indexed: 01/08/2023]
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TSC1 deletion in fibroblasts alleviates lipopolysaccharide-induced acute kidney injury. Clin Sci (Lond) 2018; 132:2087-2101. [PMID: 30185506 DOI: 10.1042/cs20180348] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2018] [Revised: 08/20/2018] [Accepted: 09/05/2018] [Indexed: 11/17/2022]
Abstract
Mechanistic target of rapamycin complex 1 (mTORC1) signaling is active in inflammation, but its involvement in septic acute kidney injury (AKI) has not been shown. mTORC1 activation (p-S6) in renal fibroblasts was increased in a mouse AKI model induced by 1.5 mg/kg lipopolysaccharide (LPS). Deletion of tuberous sclerosis complex 1 (TSC1), an mTORC1 negative regulator, in fibroblasts (Fibro-TSC1-/-) inhibited the elevation of serum creatinine and blood urea nitrogen in AKI compared with that in TSC1fl/fl control mice. Endothelin-1 (EDN1) and phospho-Jun-amino-terminal kinase (p-JNK) were up-regulated in Fibro-TSC1-/- renal fibroblasts after LPS challenge. Rapamycin, an mTORC1 inhibitor, and bosentan, an EDN1 antagonist, eliminated the difference in renal function between TSC1fl/fl and Fibro-TSC1-/- mice after LPS injection. Rapamycin restored LPS-induced up-regulation of EDN1, endothelin converting enzyme-1 (ECE1), and p-JNK in TSC1-knockdown mouse embryonic fibroblasts (MEFs). SP600125, a Jun-amino-terminal kinase (JNK) inhibitor, attenuated LPS-induced enhancement of EDN1 and ECE1 in TSC1-knockdown MEFs without a change in phospho-S6 ribosomal protein (p-S6) level. The results indicate that mTORC1-JNK-dependent up-regulation of ECE1 elevated EDN1 in TSC1-knockout renal fibroblasts and contributed to improvement of renal function in Fibro-TSC1-/- mice with LPS-induced AKI. Renal fibroblast mTORC1 plays an important role in septic AKI.
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Rungsung S, Singh TU, Rabha DJ, Kumar T, Cholenahalli Lingaraju M, Parida S, Paul A, Sahoo M, Kumar D. Luteolin attenuates acute lung injury in experimental mouse model of sepsis. Cytokine 2018; 110:333-343. [DOI: 10.1016/j.cyto.2018.03.042] [Citation(s) in RCA: 62] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2017] [Revised: 03/24/2018] [Accepted: 03/30/2018] [Indexed: 12/30/2022]
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Koutsogiannaki S, Zha H, Yuki K. Volatile Anesthetic Isoflurane Attenuates Liver Injury in Experimental Polymicrobial Sepsis Model. ACTA ACUST UNITED AC 2018; 5:63-74. [PMID: 29977977 PMCID: PMC6029873 DOI: 10.31480/2330-4871/071] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Volatile anesthetics are often administered to patients with sepsis for
procedural anesthesia or sedation in intensive care units. Sepsis still carries
significant morbidities and mortalities, and organ injuries pose major
complications. Early liver dysfunction is associated with poor outcome mainly as
a result of overwhelming neutrophil recruitment. Leukocyte function-associated
antigen-1 (LFA-1) and macrophage-1 antigen (Mac-1) are major adhesion molecules
on neutrophils and involved in neutrophil recruitment. We have previously showed
that volatile anesthetic isoflurane inhibited LFA-1 and Mac-1. Here we studied
the role of isoflurane, LFA-1 and Mac-1 on neutrophil recruitment to the liver
and liver injury using experimental polymicrobial abdominal sepsis induced by
cecal ligation and puncture (CLP) surgery. We used wild type (WT), LFA-1, Mac-1
and intercellular adhesion molecule-1 (ICAM-1) knockout (KO) mice. Following the
induction of sepsis by CLP surgery, a group of mice were exposed to isoflurane
for 2 hours. We found that Mac-1 and ICAM-1, but not LFA-1 were involved in
neutrophil recruitment to liver. Isoflurane attenuated neutrophil recruitment
and liver injury in WT and LFA-1 KO mice. Mac-1 KO mice had limited neutrophil
recruitment and liver injury, both of which were not attenuated by isoflurane
further, suggesting that isoflurane mitigated liver injury via Mac-1. Mac-1
colocalized with ICAM-1 and fibrinogen on liver tissues. In the presence of
fibrinogen Mac-1 bound ICAM-1 significantly more, while LFA-1 bound less to
ICAM-1, suggesting that Mac-1 used fibrinogen as a bridging molecule to bind
ICAM-1. In conclusion, isoflurane exposure attenuated neutrophil recruitment and
liver injury via Mac-1.
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Affiliation(s)
- Sophia Koutsogiannaki
- Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children's Hospital, Boston, MA, USA.,Department of Anaesthesia, Harvard Medical School, Boston, MA, USA
| | - Hui Zha
- Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children's Hospital, Boston, MA, USA.,Department of Anaesthesia, Harvard Medical School, Boston, MA, USA.,Department of Pediatric, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Koichi Yuki
- Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children's Hospital, Boston, MA, USA.,Department of Anaesthesia, Harvard Medical School, Boston, MA, USA
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Bolognese AC, Yang WL, Hansen LW, Denning NL, Nicastro JM, Coppa GF, Wang P. Inhibition of necroptosis attenuates lung injury and improves survival in neonatal sepsis. Surgery 2018; 164:S0039-6060(18)30096-5. [PMID: 29709367 PMCID: PMC6204110 DOI: 10.1016/j.surg.2018.02.017] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2017] [Revised: 02/09/2018] [Accepted: 02/20/2018] [Indexed: 12/16/2022]
Abstract
BACKGROUND Neonatal sepsis represents a unique therapeutic challenge owing to an immature immune system. Necroptosis is a form of programmed cell death that has been identified as an important mechanism of inflammation-induced cell death. Receptor-interacting protein kinase 1 plays a key role in mediating this process. We hypothesized that pharmacologic blockade of receptor-interacting protein kinase 1 activity would be protective in neonatal sepsis. METHODS Sepsis was induced in C57BL/6 mouse pups (5-7 days old) by intraperitoneal injection of adult cecal slurry. At 1 hour after cecal slurry injection, the receptor-interacting protein kinase 1 inhibitor necrostatin-1 (10 µg/g body weight) or vehicle (5% dimethyl sulfoxide in phosphate buffered saline) was administered via retro-orbital injection. At 20 hours after cecal slurry injection, blood and lung tissues were collected for various analyses. RESULTS At 20 hours after sepsis induction, vehicle-treated pups showed a marked increase in serum levels of interleukin 6, interleukin 1-beta, and interleukin 18 compared to sham. With necrostatin-1 treatment, serum levels of interleukin 6, interleukin 1-beta, and interleukin 18 were decreased by 77%, 81%, and 63%, respectively, compared to vehicle. In the lungs, sepsis induction resulted in a 232-, 10-, and 2.8-fold increase in interleukin 6, interleukin 1-beta, and interleukin 18 mRNA levels compared to sham, while necrostatin-1 treatment decreased these levels to 40-, 4-, and 0.8-fold, respectively. Expressions of the neutrophil chemokines keratinocyte chemoattractant and macrophage-inflammatory-protein-2 were also increased in the lungs in sepsis, while necrostatin-1 treatment decreased these levels by 81% and 61%, respectively, compared to vehicle. In addition, necrostatin-1 treatment significantly improved the lung histologic injury score and decreased lung apoptosis in septic pups. Finally, treatment with necrostatin-1 increased the 7-day survival rate from 0% in the vehicle-treated septic pups to 29% (P = .11). CONCLUSION Inhibition of receptor-interacting protein kinase 1 by necrostatin-1 decreases systemic and pulmonary inflammation, decreases lung injury, and increases survival in neonatal mice with sepsis. Targeting the necroptosis pathway might represent a new therapeutic strategy for neonatal sepsis.
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Affiliation(s)
- Alexandra C Bolognese
- Elmezzi Graduate School of Molecular Medicine, Manhasset, NY; Department of Surgery, Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY
| | - Weng-Lang Yang
- Elmezzi Graduate School of Molecular Medicine, Manhasset, NY; Department of Surgery, Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY; Center for Immunology and Inflammation, The Feinstein Institute for Medical Research, Manhasset, NY
| | - Laura W Hansen
- Department of Surgery, Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY
| | - Naomi-Liza Denning
- Elmezzi Graduate School of Molecular Medicine, Manhasset, NY; Department of Surgery, Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY
| | - Jeffrey M Nicastro
- Department of Surgery, Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY
| | - Gene F Coppa
- Department of Surgery, Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY
| | - Ping Wang
- Elmezzi Graduate School of Molecular Medicine, Manhasset, NY; Department of Surgery, Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY; Center for Immunology and Inflammation, The Feinstein Institute for Medical Research, Manhasset, NY.
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Yadav S, Pathak S, Sarikhani M, Majumdar S, Ray S, Chandrasekar BS, Adiga V, Sundaresan NR, Nandi D. Nitric oxide synthase 2 enhances the survival of mice during Salmonella Typhimurium infection-induced sepsis by increasing reactive oxygen species, inflammatory cytokines and recruitment of neutrophils to the peritoneal cavity. Free Radic Biol Med 2018; 116:73-87. [PMID: 29309892 DOI: 10.1016/j.freeradbiomed.2017.12.032] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2017] [Revised: 12/20/2017] [Accepted: 12/22/2017] [Indexed: 12/29/2022]
Abstract
Sepsis, a leading cause of death in intensive care units, is primarily caused due to an exaggerated immune response. The hyperactive inflammatory response mediated by immune cells against infectious organisms and their toxins results in host cell death and tissue damage, the hallmarks of septic shock. Therefore, molecules that modulate inflammatory responses are attractive therapeutic targets for sepsis. Nitric oxide (NO) is a signaling molecule, which is implicated in regulating diverse immune functions. Although, the protective roles of NO in infectious diseases are well documented, its importance in sepsis is controversial. In the present study, the effects of intra-peritoneal injection of mice with Salmonella Typhimurium, a Gram-negative intracellular pathogen, were studied which leads to a rapid upregulation of serum cytokines and infiltration of neutrophils to the peritoneal cavity. Surprisingly, the induction of inflammatory cytokines and chemokines, e.g. IL6 and CCL2, and the infiltration of neutrophils into the peritoneal cavity are mitigated in mice lacking Nitric oxide synthase 2 (NOS2). The reduced inflammatory response in Nos2-/- mice is accompanied by greater bacterial burden in the peritoneal cavity, lower thymic atrophy, higher liver damage and cardiovascular dysfunction followed by decreased survival. However, no significant differences are observed in other responses between C57BL/6 wild type (WT) and Nos2-/- mice: induction of glucocorticoids, phagocytic ability and apoptosis of peritoneal cells. This study clearly highlights the NOS2-dependent and -independent responses in this mouse model of peritonitis induced sepsis. Importantly, pre-treatment of Nos2-/- mice with DETA-NO, a NO donor, upon infection, restores neutrophil recruitment, reduces bacterial numbers in the peritoneal cavity, improves liver and cardio-vascular function and enhances survival. Interestingly, DETA-NO treatment does not significantly increase the survival of infected WT mice. The implications of these results and the complex roles of NO as a target molecule during sepsis are discussed.
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Affiliation(s)
- Shikha Yadav
- Department of Biochemistry, Indian Institute of Science, Bangalore 560012, India
| | - Sanmoy Pathak
- Department of Biochemistry, Indian Institute of Science, Bangalore 560012, India
| | - Mohsen Sarikhani
- Department of Microbiology & Cell Biology, Indian Institute of Science, Bangalore 560012, India
| | - Shamik Majumdar
- Department of Biochemistry, Indian Institute of Science, Bangalore 560012, India
| | - Semanti Ray
- Department of Biochemistry, Indian Institute of Science, Bangalore 560012, India
| | | | - Vasista Adiga
- Centre for Infectious Disease Research, Indian Institute of Science, Bangalore 560012, India
| | - Nagalingam R Sundaresan
- Department of Microbiology & Cell Biology, Indian Institute of Science, Bangalore 560012, India
| | - Dipankar Nandi
- Department of Biochemistry, Indian Institute of Science, Bangalore 560012, India; Centre for Infectious Disease Research, Indian Institute of Science, Bangalore 560012, India.
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Ode Y, Aziz M, Wang P. CIRP increases ICAM-1 + phenotype of neutrophils exhibiting elevated iNOS and NETs in sepsis. J Leukoc Biol 2018; 103:693-707. [PMID: 29345380 DOI: 10.1002/jlb.3a0817-327rr] [Citation(s) in RCA: 72] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2017] [Revised: 12/15/2017] [Accepted: 12/16/2017] [Indexed: 12/29/2022] Open
Abstract
Sepsis represents uncontrolled inflammation due to an infection. Cold-inducible RNA-binding protein (CIRP) is a stress-induced damage-associated molecular pattern (DAMP). A subset of neutrophils expressing ICAM-1+ neutrophils was previously shown to produce high levels of reactive oxygen species. The role of CIRP for the development and function of ICAM-1+ neutrophils during sepsis is unknown. We hypothesize that CIRP induces ICAM-1 expression in neutrophils causing injury to the lungs during sepsis. Using a mouse model of cecal ligation and puncture (CLP)-induced sepsis, we found increased expression of CIRP and higher frequencies and numbers of ICAM-1+ neutrophils in the lungs. Conversely, the CIRP-/- mice showed significant inhibition in the frequencies and numbers of ICAM-1+ neutrophils in the lungs compared to wild-type (WT) mice in sepsis. In vitro treatment of bone marrow-derived neutrophils (BMDN) with recombinant murine CIRP (rmCIRP) significantly increased ICAM-1+ phenotype in a time- and dose-dependent manner. The effect of rmCIRP on increasing frequencies of ICAM-1+ neutrophils was significantly attenuated in BMDN treated with anti-TLR4 Ab or NF-κB inhibitor compared, respectively, with BMDN treated with isotype IgG or DMSO. The frequencies of iNOS producing and neutrophil extracellular traps (NETs) forming phenotypes in rmCIRP-treated ICAM-1+ BMDN were significantly higher than those in ICAM-1- BMDN. Following sepsis the ICAM-1+ neutrophils in the lungs showed significantly higher levels of iNOS and NETs compared to ICAM-1- neutrophils. We further revealed that ICAM-1 and NETs were co-localized in the neutrophils treated with rmCIRP. CIRP-/- mice showed significant improvement in their survival outcome (78% survival) over that of WT mice (48% survival) in sepsis. Thus, CIRP could be a novel therapeutic target for regulating iNOS producing and NETs forming ICAM-1+ neutrophils in the lungs during sepsis.
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Affiliation(s)
- Yasumasa Ode
- Center for Immunology and Inflammation, The Feinstein Institute for Medical Research, Manhasset, New York, USA
| | - Monowar Aziz
- Center for Immunology and Inflammation, The Feinstein Institute for Medical Research, Manhasset, New York, USA
| | - Ping Wang
- Center for Immunology and Inflammation, The Feinstein Institute for Medical Research, Manhasset, New York, USA.,Department of Surgery and Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Manhasset, New York, USA
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Ramadass M, Catz SD. Molecular mechanisms regulating secretory organelles and endosomes in neutrophils and their implications for inflammation. Immunol Rev 2017; 273:249-65. [PMID: 27558339 DOI: 10.1111/imr.12452] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Neutrophils constitute the first line of cellular defense against invading microorganisms and modulate the subsequent innate and adaptive immune responses. In order to execute a rapid and precise response to infections, neutrophils rely on preformed effector molecules stored in a variety of intracellular granules. Neutrophil granules contain microbicidal factors, the membrane-bound components of the respiratory burst oxidase, membrane-bound adhesion molecules, and receptors that facilitate the execution of all neutrophil functions including adhesion, transmigration, phagocytosis, degranulation, and neutrophil extracellular trap formation. The rapid mobilization of intracellular organelles is regulated by vesicular trafficking mechanisms controlled by effector molecules that include small GTPases and their interacting proteins. In this review, we focus on recent discoveries of mechanistic processes that are at center stage of the regulation of neutrophil function, highlighting the discrete and selective pathways controlled by trafficking modulators. In particular, we describe novel pathways controlled by the Rab27a effectors JFC1 and Munc13-4 in the regulation of degranulation, reactive oxygen species and neutrophil extracellular trap production, and endolysosomal signaling. Finally, we discuss the importance of understanding these molecular mechanisms in order to design novel approaches to modulate neutrophil-mediated inflammatory processes in a targeted fashion.
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Affiliation(s)
- Mahalakshmi Ramadass
- Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA, USA
| | - Sergio D Catz
- Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA, USA
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Kelly MEM, Lehmann C, Zhou J. The Endocannabinoid System in Local and Systemic Inflammation. ACTA ACUST UNITED AC 2017. [DOI: 10.4199/c00151ed1v01y201702isp074] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
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Abstract
Sepsis remains a major clinical problem with high morbidity and mortality. As new inflammatory mediators are characterized, it is important to understand their roles in sepsis. Interleukin 33 (IL-33) is a recently described member of the IL-1 family that is widely expressed in cells of barrier tissues. Upon tissue damage, IL-33 is released as an alarmin and activates various types of cells of both the innate and adaptive immune system through binding to the ST2/IL-1 receptor accessory protein complex. IL-33 has apparent pleiotropic functions in many disease models, with its actions strongly shaped by the local microenvironment. Recent studies have established a role for the IL-33-ST2 axis in the initiation and perpetuation of inflammation during endotoxemia, but its roles in sepsis appear to be organism and model dependent. In this review, we focus on the recent advances in understanding the role of the IL-33/ST2 axis in sepsis.
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Affiliation(s)
- Hui Xu
- Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213 USA.,State Key Laboratory of Oral Diseases, Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041 China
| | - Heth R Turnquist
- Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213 USA.,Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213 USA
| | - Rosemary Hoffman
- Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213 USA.,State Key Laboratory of Oral Diseases, Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041 China
| | - Timothy R Billiar
- Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213 USA
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Jacobs L, Wong HR. Emerging infection and sepsis biomarkers: will they change current therapies? Expert Rev Anti Infect Ther 2016; 14:929-41. [PMID: 27533847 PMCID: PMC5087989 DOI: 10.1080/14787210.2016.1222272] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2016] [Accepted: 08/05/2016] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Sepsis is a heterogeneous syndrome characterized by both immune hyperactivity and relative immune suppression. Biomarkers have the potential to improve recognition and management of sepsis through three main applications: diagnosis, monitoring response to treatment, and stratifying patients based on prognosis or underlying biological response. AREAS COVERED This review focuses on specific examples of well-studied, evidence-supported biomarkers, and discusses their role in clinical practice with special attention to antibiotic stewardship and cost-effectiveness. Biomarkers were selected based on availability of robust prospective trials and meta-analyses which supported their role as emerging tools to improve the clinical management of sepsis. Expert commentary: Great strides have been made in candidate sepsis biomarker discovery and testing, with the biomarkers in this review showing promise. Yet sepsis remains a dynamic illness with a great degree of biological heterogeneity - heterogeneity which may be further resolved by recently discovered gene expression-based endotypes in septic shock.
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Affiliation(s)
- Lauren Jacobs
- Department of Pediatrics, Division of Critical Care Medicine, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave., Cincinnati OH, 45229, , Tel: 513-636-4529, Fax: 513-636-4267
| | - Hector R Wong
- Professor of Pediatrics, Director, Critical Care Medicine, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave., Cincinnati, OH 45229, (corresponding author), Tel: 513-636-4529, Fax: 513-636-4267
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Biron BM, Chung CS, O'Brien XM, Chen Y, Reichner JS, Ayala A. Cl-Amidine Prevents Histone 3 Citrullination and Neutrophil Extracellular Trap Formation, and Improves Survival in a Murine Sepsis Model. J Innate Immun 2016; 9:22-32. [PMID: 27622642 DOI: 10.1159/000448808] [Citation(s) in RCA: 126] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2016] [Accepted: 08/02/2016] [Indexed: 01/24/2023] Open
Abstract
Sepsis refers to the presence of a serious infection that correlates with systemic and uncontrolled immune activation. Posttranslational histone modification plays an important role in chromatin decondensation, which is regulated by citrullination. Citrullinated histone H3 (H3cit) has been identified as a component of neutrophil extracellular traps (NETs), which are released into the extracellular space as part of the neutrophil response to infection. The conversion of arginine to citrulline residues on histones is catalyzed by peptidylarginine deiminase 4 (PAD4). This study's goals were to characterize the presence of PAD4-catalyzed H3cit and NET formation during the onset of sepsis and elucidate the effects on the immune response when this mechanism of action is blocked. Adult C57BL/6 male mice were treated with Cl-amidine, an inhibitor of PAD4, 1 h prior to sepsis induced by cecal ligation and puncture (CLP). Twenty-four hours after CLP, cytokine levels, H3cit protein expression, neutrophil counts, and NET production were evaluated in the peritoneal cavity. Survival studies were also performed. Here we demonstrate that Cl-amidine treatment prior to CLP improves overall survival in sepsis and the abrogation of PAD4 has minimal effects on the proinflammatory immune response to sepsis, while it has no effect on overall neutrophil migration to the peritoneum.
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Affiliation(s)
- Bethany M Biron
- Division of Surgical Research, Department of Surgery, Rhode Island Hospital, Brown University, Providence, R.I., USA
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Wang Y, Wang F, Yang D, Tang X, Li H, Lv X, Lu D, Wang H. Berberine in combination with yohimbine attenuates sepsis-induced neutrophil tissue infiltration and multiorgan dysfunction partly via IL-10-mediated inhibition of CCR2 expression in neutrophils. Int Immunopharmacol 2016; 35:217-225. [PMID: 27082997 DOI: 10.1016/j.intimp.2016.03.041] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2015] [Revised: 03/16/2016] [Accepted: 03/28/2016] [Indexed: 02/05/2023]
Abstract
Infiltration of activated neutrophils into the vital organs contributes to the multiple organ dysfunctions in sepsis. In the present study, we investigated the effects of berberine in combination with yohimbine (BY) on neutrophil tissue infiltration and multiple organ damage during sepsis, and further elucidated the involved mechanisms. Sepsis was induced in mice by cecal ligation and puncture (CLP). BY or CCR2 antagonist was administered 2h after CLP, and anti-IL-10 antibody (IL-10 Ab) or control IgG was injected intraperitoneally just before BY treatment. We found that IL-10 production was enhanced by BY therapy in septic mice. BY significantly attenuated neutrophil tissue infiltration and multiple organ injury in CLP-challenged mice, all of which were completely reversed by IL-10 Ab pretreatment. The levels of KC, MCP-1, MIP-1α and MIP-2 in the lung, liver and kidney were markedly increased 6h after CLP. BY reduced the tissue concentrations of these chemokines in septic mice, but IL-10 Ab pretreatment did not completely eliminate these inhibitory effects of BY. Particularly, dramatically increased CCR2 expression in circulating neutrophils of septic mice was reduced by BY and this effect was completely abolished by IL-10 Ab pretreatment. Furthermore, CCR2 antagonist also inhibited lung and renal injury and neutrophil infiltration in septic mice. Taken together, our data strongly suggest that BY therapy attenuates neutrophil tissue infiltration and multiple organ injury in septic mice, at least in part, via IL-10-mediated inhibition of CCR2 expression in circulating neutrophils.
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Affiliation(s)
- Yuan Wang
- Department of Pathophysiology, Key Laboratory of State Administration of Traditional Chinese Medicine of the People's Republic of China, School of Medicine, Jinan University, Guangzhou 510632, Guangdong, China
| | - Faqiang Wang
- Department of Pathophysiology, Key Laboratory of State Administration of Traditional Chinese Medicine of the People's Republic of China, School of Medicine, Jinan University, Guangzhou 510632, Guangdong, China
| | - Duomeng Yang
- Department of Pathophysiology, Key Laboratory of State Administration of Traditional Chinese Medicine of the People's Republic of China, School of Medicine, Jinan University, Guangzhou 510632, Guangdong, China
| | - Xiangxu Tang
- Department of Pathophysiology, Key Laboratory of State Administration of Traditional Chinese Medicine of the People's Republic of China, School of Medicine, Jinan University, Guangzhou 510632, Guangdong, China
| | - Hongmei Li
- Department of Pathophysiology, Key Laboratory of State Administration of Traditional Chinese Medicine of the People's Republic of China, School of Medicine, Jinan University, Guangzhou 510632, Guangdong, China
| | - Xiuxiu Lv
- Department of Pathophysiology, Key Laboratory of State Administration of Traditional Chinese Medicine of the People's Republic of China, School of Medicine, Jinan University, Guangzhou 510632, Guangdong, China
| | - Daxiang Lu
- Department of Pathophysiology, Key Laboratory of State Administration of Traditional Chinese Medicine of the People's Republic of China, School of Medicine, Jinan University, Guangzhou 510632, Guangdong, China
| | - Huadong Wang
- Department of Pathophysiology, Key Laboratory of State Administration of Traditional Chinese Medicine of the People's Republic of China, School of Medicine, Jinan University, Guangzhou 510632, Guangdong, China.
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Sônego F, Castanheira FVES, Ferreira RG, Kanashiro A, Leite CAVG, Nascimento DC, Colón DF, Borges VDF, Alves-Filho JC, Cunha FQ. Paradoxical Roles of the Neutrophil in Sepsis: Protective and Deleterious. Front Immunol 2016; 7:155. [PMID: 27199981 PMCID: PMC4844928 DOI: 10.3389/fimmu.2016.00155] [Citation(s) in RCA: 160] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2016] [Accepted: 04/11/2016] [Indexed: 12/16/2022] Open
Abstract
Sepsis, an overwhelming inflammatory response syndrome secondary to infection, is one of the costliest and deadliest medical conditions worldwide. Neutrophils are classically considered to be essential players in the host defense against invading pathogens. However, several investigations have shown that impairment of neutrophil migration to the site of infection, also referred to as neutrophil paralysis, occurs during severe sepsis, resulting in an inability of the host to contain and eliminate the infection. On the other hand, the neutrophil antibacterial arsenal contributes to tissue damage and the development of organ dysfunction during sepsis. In this review, we provide an overview of the main events in which neutrophils play a beneficial or deleterious role in the outcome of sepsis.
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Affiliation(s)
- Fabiane Sônego
- Departamento de Farmacologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo , Ribeirão Preto , Brazil
| | | | - Raphael Gomes Ferreira
- Departamento de Farmacologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo , Ribeirão Preto , Brazil
| | - Alexandre Kanashiro
- Departamento de Farmacologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo , Ribeirão Preto , Brazil
| | | | - Daniele Carvalho Nascimento
- Departamento de Farmacologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo , Ribeirão Preto , Brazil
| | - David Fernando Colón
- Departamento de Bioquímica e Imunologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo , Ribeirão Preto , Brazil
| | - Vanessa de Fátima Borges
- Departamento de Farmacologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo , Ribeirão Preto , Brazil
| | - José Carlos Alves-Filho
- Departamento de Farmacologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo , Ribeirão Preto , Brazil
| | - Fernando Queiróz Cunha
- Departamento de Farmacologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo , Ribeirão Preto , Brazil
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Rimmelé T, Payen D, Cantaluppi V, Marshall J, Gomez H, Gomez A, Murray P, Kellum JA. IMMUNE CELL PHENOTYPE AND FUNCTION IN SEPSIS. Shock 2016; 45:282-91. [PMID: 26529661 PMCID: PMC4752878 DOI: 10.1097/shk.0000000000000495] [Citation(s) in RCA: 129] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Cells of the innate and adaptive immune systems play a critical role in the host response to sepsis. Moreover, their accessibility for sampling and their capacity to respond dynamically to an acute threat increases the possibility that leukocytes might serve as a measure of a systemic state of altered responsiveness in sepsis.The working group of the 14th Acute Dialysis Quality Initiative (ADQI) conference sought to obtain consensus on the characteristic functional and phenotypic changes in cells of the innate and adaptive immune system in the setting of sepsis. Techniques for the study of circulating leukocytes were also reviewed and the impact on cellular phenotypes and leukocyte function of nonextracorporeal treatments and extracorporeal blood purification therapies proposed for sepsis was analyzed.A large number of alterations in the expression of distinct neutrophil and monocyte surface markers have been reported in septic patients. The most consistent alteration seen in septic neutrophils is their activation of a survival program that resists apoptotic death. Reduced expression of HLA-DR is a characteristic finding on septic monocytes, but monocyte antimicrobial function does not appear to be significantly altered in sepsis. Regarding adaptive immunity, sepsis-induced apoptosis leads to lymphopenia in patients with septic shock and it involves all types of T cells (CD4, CD8, and Natural Killer) except T regulatory cells, thus favoring immunosuppression. Finally, numerous promising therapies targeting the host immune response to sepsis are under investigation. These potential treatments can have an effect on the number of immune cells, the proportion of cell subtypes, and the cell function.
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Affiliation(s)
- Thomas Rimmelé
- Anesthesiology and Critical Care Medicine, Edouard Herriot Hospital, Hospices Civils de Lyon, University Claude Bernard Lyon 1, Lyon, France
| | - Didier Payen
- Department of Anesthesiology & Critical Care and UMR INSERM 1160; Lariboisière Hospital, AP-HP and University Paris 7, Sorbonne Paris Cité, Paris, France
| | - Vincenzo Cantaluppi
- Nephrology, Dialysis and Kidney Transplantation Unit, Department of Medical Sciences, “Citta' della Salute e della Scienza di Torino- Molinette” University Hospital, Torino, Italy
| | - John Marshall
- Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario Canada
| | - Hernando Gomez
- Center for Critical Care Nephrology; The CRISMA (Clinical Research, Investigation, and Systems Modeling of Acute Illness) Center, Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Alonso Gomez
- Academia Colombiana de Medicina Critica (ACOMEC)
- Division of Critical Care Medicine, Clínica Palermo, Bogotá, Colombia
| | | | - John A. Kellum
- Center for Critical Care Nephrology; The CRISMA (Clinical Research, Investigation, and Systems Modeling of Acute Illness) Center, Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
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