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1
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Mak KM, Shekhar AC. Lipopolysaccharide, arbiter of the gut-liver axis, modulates hepatic cell pathophysiology in alcoholism. Anat Rec (Hoboken) 2025; 308:975-1004. [PMID: 39166429 DOI: 10.1002/ar.25562] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Revised: 07/18/2024] [Accepted: 08/06/2024] [Indexed: 08/22/2024]
Abstract
Over the last four decades, clinical research and experimental studies have established that lipopolysaccharide (LPS)-a component of the outer membrane of gram-negative bacteria-is a potent hepatotoxic molecule in humans and animals. Alcohol abuse is commonly associated with LPS endotoxemia. This review highlights LPS molecular structures and modes of release from bacteria, plasma LPS concentrations, induction of microbiota dysbiosis, disruption of gut epithelial barrier, and translocation of LPS into the portal circulation impacting the pathophysiology of hepatic cells via the gut-liver axis. We describe and illustrate the portal vein circulation and its distributaries draining the gastrointestinal tract. We also elaborate on the gut-liver axis coupled with enterohepatic circulation that represents a bidirectional communication between the gut and liver. The review also updates the data on how circulating LPS is cleared in a coordinated effort between Kupffer cells, hepatocytes, and liver sinusoidal endothelial cells. Significantly, the article reviews and updates the modes/mechanisms of action by which LPS mediates the diverse pathophysiology of Kupffer cells, hepatocytes, sinusoidal endothelial cells, and hepatic stellate cells primarily in association with alcohol consumption. Specifically, we review the intricate linkages between ethanol, microbiota dysbiosis, LPS production, gut-liver axis, and pathophysiology of various hepatic cells. The maintenance of the gut barrier structural and functional integrity and microbiome homeostasis is essential in mitigating alcoholic liver disease and improving liver health.
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Affiliation(s)
- Ki M Mak
- Department of Medical Education, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Aditya C Shekhar
- Department of Medical Education, Icahn School of Medicine at Mount Sinai, New York, New York, USA
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2
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Graham CT, Gordon S, Kubes P. A historical perspective of Kupffer cells in the context of infection. Cell Tissue Res 2024:10.1007/s00441-024-03924-4. [PMID: 39392500 DOI: 10.1007/s00441-024-03924-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Accepted: 10/02/2024] [Indexed: 10/12/2024]
Abstract
The Kupffer cell was first discovered by Karl Wilhelm von Kupffer in 1876, labeling them as "Sternzellen." Since their discovery as the primary macrophages of the liver, researchers have gradually gained an in-depth understanding of the identity, functions, and influential role of Kupffer cells, particularly in infection. It is becoming clear that Kupffer cells perform important tissue-specific functions in homeostasis and disease. Stationary in the sinusoids of the liver, Kupffer cells have a high phagocytic capacity and are adept in clearing the bloodstream of foreign material, toxins, and pathogens. Thus, they are indispensable to host defense and prevent the dissemination of bacteria during infections. To highlight the importance of this cell, this review will explore the history of the Kupffer cell in the context of infection beginning with its discovery to the present day.
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Affiliation(s)
- Carolyn T Graham
- Department of Physiology and Pharmacology, University of Calgary, 3330 Hospital Drive NW, Calgary, AB, T2N 4N1, Canada.
| | - Siamon Gordon
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, 259 Wenhua 1st Road Guishan Dist., Taoyuan, Taiwan
| | - Paul Kubes
- Department of Physiology and Pharmacology, University of Calgary, 3330 Hospital Drive NW, Calgary, AB, T2N 4N1, Canada
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3
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Ahamed F, Eppler N, Jones E, Zhang Y. Understanding Macrophage Complexity in Metabolic Dysfunction-Associated Steatotic Liver Disease: Transitioning from the M1/M2 Paradigm to Spatial Dynamics. LIVERS 2024; 4:455-478. [PMID: 39328386 PMCID: PMC11426415 DOI: 10.3390/livers4030033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 09/28/2024] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) encompasses metabolic dysfunction-associated fatty liver (MASL) and metabolic dysfunction-associated steatohepatitis (MASH), with MASH posing a risk of progression to cirrhosis and hepatocellular carcinoma (HCC). The global prevalence of MASLD is estimated at approximately a quarter of the population, with significant healthcare costs and implications for liver transplantation. The pathogenesis of MASLD involves intrahepatic liver cells, extrahepatic components, and immunological aspects, particularly the involvement of macrophages. Hepatic macrophages are a crucial cellular component of the liver and play important roles in liver function, contributing significantly to tissue homeostasis and swift responses during pathophysiological conditions. Recent advancements in technology have revealed the remarkable heterogeneity and plasticity of hepatic macrophage populations and their activation states in MASLD, challenging traditional classification methods like the M1/M2 paradigm and highlighting the coexistence of harmful and beneficial macrophage phenotypes that are dynamically regulated during MASLD progression. This complexity underscores the importance of considering macrophage heterogeneity in therapeutic targeting strategies, including their distinct ontogeny and functional phenotypes. This review provides an overview of macrophage involvement in MASLD progression, combining traditional paradigms with recent insights from single-cell analysis and spatial dynamics. It also addresses unresolved questions and challenges in this area.
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Affiliation(s)
- Forkan Ahamed
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, MS 1018, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA
| | - Natalie Eppler
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, MS 1018, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA
| | - Elizabeth Jones
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, MS 1018, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA
| | - Yuxia Zhang
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, MS 1018, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA
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4
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Mata-Martínez E, Ramírez-Ledesma MG, Vázquez-Victorio G, Hernández-Muñoz R, Díaz-Muñoz M, Vázquez-Cuevas FG. Purinergic Signaling in Non-Parenchymal Liver Cells. Int J Mol Sci 2024; 25:9447. [PMID: 39273394 PMCID: PMC11394727 DOI: 10.3390/ijms25179447] [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: 08/15/2024] [Revised: 08/27/2024] [Accepted: 08/29/2024] [Indexed: 09/15/2024] Open
Abstract
Purinergic signaling has emerged as an important paracrine-autocrine intercellular system that regulates physiological and pathological processes in practically all organs of the body. Although this system has been thoroughly defined since the nineties, recent research has made substantial advances regarding its role in aspects of liver physiology. However, most studies have mainly targeted the entire organ, 70% of which is made up of parenchymal cells or hepatocytes. Because of its physiological role, the liver is exposed to toxic metabolites, such as xenobiotics, drugs, and fatty acids, as well as to pathogens such as viruses and bacteria. Under injury conditions, all cell types within the liver undergo adaptive changes. In this context, the concentration of extracellular ATP has the potential to increase dramatically. Indeed, this purinergic response has not been studied in sufficient detail in non-parenchymal liver cells. In the present review, we systematize the physiopathological adaptations related to the purinergic system in chronic liver diseases of non-parenchymal liver cells, such as hepatic stellate cells, Kupffer cells, sinusoidal endothelial cells, and cholangiocytes. The role played by non-parenchymal liver cells in these circumstances will undoubtedly be strategic in understanding the regenerative activities that support the viability of this organ under stressful conditions.
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Affiliation(s)
- Esperanza Mata-Martínez
- Departamento de Biología Celular y Desarrollo, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México (UNAM), Ciudad Universitaria, Mexico City 04510, Mexico
| | - María Guadalupe Ramírez-Ledesma
- Departamento de Neurobiología Celular y Molecular, Instituto de Neurobiología, Universidad Nacional Autónoma de México (UNAM), Boulevard Juriquilla #3001, Querétaro 76230, Mexico
| | - Genaro Vázquez-Victorio
- Departamento de Física, Facultad de Ciencias, Universidad Nacional Autónoma de México (UNAM), Circuito Exterior S/N, Ciudad Universitaria, Mexico City 04510, Mexico
| | - Rolando Hernández-Muñoz
- Departamento de Biología Celular y Desarrollo, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México (UNAM), Ciudad Universitaria, Mexico City 04510, Mexico
| | - Mauricio Díaz-Muñoz
- Departamento de Neurobiología Celular y Molecular, Instituto de Neurobiología, Universidad Nacional Autónoma de México (UNAM), Boulevard Juriquilla #3001, Querétaro 76230, Mexico
| | - Francisco G Vázquez-Cuevas
- Departamento de Neurobiología Celular y Molecular, Instituto de Neurobiología, Universidad Nacional Autónoma de México (UNAM), Boulevard Juriquilla #3001, Querétaro 76230, Mexico
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Miyamoto Y, Kikuta J, Matsui T, Hasegawa T, Fujii K, Okuzaki D, Liu YC, Yoshioka T, Seno S, Motooka D, Uchida Y, Yamashita E, Kobayashi S, Eguchi H, Morii E, Tryggvason K, Shichita T, Kayama H, Atarashi K, Kunisawa J, Honda K, Takeda K, Ishii M. Periportal macrophages protect against commensal-driven liver inflammation. Nature 2024; 629:901-909. [PMID: 38658756 DOI: 10.1038/s41586-024-07372-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Accepted: 04/02/2024] [Indexed: 04/26/2024]
Abstract
The liver is the main gateway from the gut, and the unidirectional sinusoidal flow from portal to central veins constitutes heterogenous zones, including the periportal vein (PV) and the pericentral vein zones1-5. However, functional differences in the immune system in each zone remain poorly understood. Here intravital imaging revealed that inflammatory responses are suppressed in PV zones. Zone-specific single-cell transcriptomics detected a subset of immunosuppressive macrophages enriched in PV zones that express high levels of interleukin-10 and Marco, a scavenger receptor that sequesters pro-inflammatory pathogen-associated molecular patterns and damage-associated molecular patterns, and consequently suppress immune responses. Induction of Marco+ immunosuppressive macrophages depended on gut microbiota. In particular, a specific bacterial family, Odoribacteraceae, was identified to induce this macrophage subset through its postbiotic isoallolithocholic acid. Intestinal barrier leakage resulted in inflammation in PV zones, which was markedly augmented in Marco-deficient conditions. Chronic liver inflammatory diseases such as primary sclerosing cholangitis (PSC) and non-alcoholic steatohepatitis (NASH) showed decreased numbers of Marco+ macrophages. Functional ablation of Marco+ macrophages led to PSC-like inflammatory phenotypes related to colitis and exacerbated steatosis in NASH in animal experimental models. Collectively, commensal bacteria induce Marco+ immunosuppressive macrophages, which consequently limit excessive inflammation at the gateway of the liver. Failure of this self-limiting system promotes hepatic inflammatory disorders such as PSC and NASH.
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Affiliation(s)
- Yu Miyamoto
- Department of Immunology and Cell Biology, Graduate School of Medicine and Frontier Biosciences, Osaka University, Osaka, Japan
- WPI-Immunology Frontier Research Center, Osaka University, Osaka, Japan
- Life-omics Research Division, Institute for Open and Transdisciplinary Research Initiative, Osaka University, Osaka, Japan
| | - Junichi Kikuta
- Department of Immunology and Cell Biology, Graduate School of Medicine and Frontier Biosciences, Osaka University, Osaka, Japan
- WPI-Immunology Frontier Research Center, Osaka University, Osaka, Japan
- Life-omics Research Division, Institute for Open and Transdisciplinary Research Initiative, Osaka University, Osaka, Japan
- Laboratory of Bioimaging and Drug Discovery, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan
| | - Takahiro Matsui
- Department of Immunology and Cell Biology, Graduate School of Medicine and Frontier Biosciences, Osaka University, Osaka, Japan
- Department of Pathology, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Tetsuo Hasegawa
- Department of Immunology and Cell Biology, Graduate School of Medicine and Frontier Biosciences, Osaka University, Osaka, Japan
| | - Kentaro Fujii
- Department of Immunology and Cell Biology, Graduate School of Medicine and Frontier Biosciences, Osaka University, Osaka, Japan
- WPI-Immunology Frontier Research Center, Osaka University, Osaka, Japan
- Life-omics Research Division, Institute for Open and Transdisciplinary Research Initiative, Osaka University, Osaka, Japan
| | - Daisuke Okuzaki
- WPI-Immunology Frontier Research Center, Osaka University, Osaka, Japan
- Genome Information Research Center, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
| | - Yu-Chen Liu
- WPI-Immunology Frontier Research Center, Osaka University, Osaka, Japan
- Genome Information Research Center, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
| | - Takuya Yoshioka
- Laboratory of Vaccine Materials, Center for Vaccine and Adjuvant Research, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan
| | - Shigeto Seno
- Department of Bioinformatic Engineering, Graduate School of Information Science and Technology, Osaka University, Osaka, Japan
| | - Daisuke Motooka
- WPI-Immunology Frontier Research Center, Osaka University, Osaka, Japan
- Genome Information Research Center, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
| | - Yutaka Uchida
- Department of Immunology and Cell Biology, Graduate School of Medicine and Frontier Biosciences, Osaka University, Osaka, Japan
- WPI-Immunology Frontier Research Center, Osaka University, Osaka, Japan
- Life-omics Research Division, Institute for Open and Transdisciplinary Research Initiative, Osaka University, Osaka, Japan
- Laboratory of Bioimaging and Drug Discovery, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan
| | - Erika Yamashita
- Department of Immunology and Cell Biology, Graduate School of Medicine and Frontier Biosciences, Osaka University, Osaka, Japan
- WPI-Immunology Frontier Research Center, Osaka University, Osaka, Japan
- Life-omics Research Division, Institute for Open and Transdisciplinary Research Initiative, Osaka University, Osaka, Japan
| | - Shogo Kobayashi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Hidetoshi Eguchi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Eiichi Morii
- Department of Pathology, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Karl Tryggvason
- Cardiovascular and Metabolic Disorders Program, Duke-NUS, Duke-NUS Medical School, Singapore, Singapore
| | - Takashi Shichita
- Laboratory for Neuroinflammation and Repair, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan
| | - Hisako Kayama
- WPI-Immunology Frontier Research Center, Osaka University, Osaka, Japan
- Department of Microbiology and Immunology, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Koji Atarashi
- Department of Microbiology and Immunology, School of Medicine, Keio University, Tokyo, Japan
| | - Jun Kunisawa
- Laboratory of Vaccine Materials, Center for Vaccine and Adjuvant Research, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan
| | - Kenya Honda
- Department of Microbiology and Immunology, School of Medicine, Keio University, Tokyo, Japan
| | - Kiyoshi Takeda
- WPI-Immunology Frontier Research Center, Osaka University, Osaka, Japan
- Department of Microbiology and Immunology, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Masaru Ishii
- Department of Immunology and Cell Biology, Graduate School of Medicine and Frontier Biosciences, Osaka University, Osaka, Japan.
- WPI-Immunology Frontier Research Center, Osaka University, Osaka, Japan.
- Life-omics Research Division, Institute for Open and Transdisciplinary Research Initiative, Osaka University, Osaka, Japan.
- Laboratory of Bioimaging and Drug Discovery, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan.
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Chen L, Guo W, Mao C, Shen J, Wan M. Liver fibrosis: pathological features, clinical treatment and application of therapeutic nanoagents. J Mater Chem B 2024; 12:1446-1466. [PMID: 38265305 DOI: 10.1039/d3tb02790b] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2024]
Abstract
Liver fibrosis is a reversible damage-repair response, the pathological features of which mainly include damage to hepatocytes, sinusoid capillarization, hepatic stellate cells activation, excessive accumulation of extracellular matrix and inflammatory response. Although some treatments (including drugs and stem cell therapy) for these pathological features have been shown to be effective, more clinical trials are needed to confirm their effectiveness. In recent years, nanomaterials-based therapies have emerged as an innovative and promising alternative to traditional drugs, being explored for the treatment of liver fibrosis diseases. Natural nanomaterials (including extracellular vesicles) and synthetic nanomaterials (including inorganic nanomaterials and organic nanomaterials) are developed to facilitate drug targeting delivery and combination therapy. In this review, the pathological features of liver fibrosis and the current anti-fibrosis drugs in clinical trials are briefly introduced, followed by a detailed introduction of the therapeutic nanoagents for the precise delivery of anti-fibrosis drugs. Finally, the future development trend in this field is discussed.
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Affiliation(s)
- Lin Chen
- National and Local Joint Engineering Research Center of Biomedical Functional Materials, School of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210023, China.
| | - Wenyan Guo
- National and Local Joint Engineering Research Center of Biomedical Functional Materials, School of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210023, China.
| | - Chun Mao
- National and Local Joint Engineering Research Center of Biomedical Functional Materials, School of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210023, China.
| | - Jian Shen
- National and Local Joint Engineering Research Center of Biomedical Functional Materials, School of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210023, China.
| | - Mimi Wan
- National and Local Joint Engineering Research Center of Biomedical Functional Materials, School of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210023, China.
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7
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Li Y, Moein Moghimi S, Simberg D. Complement-dependent uptake of nanoparticles by blood phagocytes: brief overview and perspective. Curr Opin Biotechnol 2024; 85:103044. [PMID: 38091875 PMCID: PMC11214757 DOI: 10.1016/j.copbio.2023.103044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Accepted: 11/22/2023] [Indexed: 02/09/2024]
Abstract
Immune recognition and uptake of nanoparticles remain the hot topic in nanomedicine research. Complement is the central player in the immune recognition of engineered nanoparticles. Here, we summarize the accumulated knowledge on the role of complement in the interactions of nanomaterials with blood phagocytes. We describe the interplay between surface properties, complement opsonization, and immune uptake, primarily of iron oxide nanoparticles. We discuss the rigor of the published research and further identify the following knowledge gaps: 1) the role of complement in the variability of uptake of nanomaterials in healthy and diseased subjects, and 2) modulation of complement interactions to improve the performance of nanomaterials. Addressing these gaps is critical to improving translational chances of nanomaterials for drug delivery and imaging applications.
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Affiliation(s)
- Yue Li
- Translational Bio-Nanosciences Laboratory, USA; Department of Pharmaceutical Sciences, The Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Seyed Moein Moghimi
- School of Pharmacy, Newcastle University, Newcastle upon Tyne NE1 7RU, UK; Translational and Clinical Research Institute, Faculty of Health and Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK; Colorado Center for Nanomedicine and Nanosafety, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Dmitri Simberg
- Translational Bio-Nanosciences Laboratory, USA; Department of Pharmaceutical Sciences, The Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, USA; Colorado Center for Nanomedicine and Nanosafety, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
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8
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Sinha S, Hassan N, Schwartz RE. Organelle stress and alterations in interorganelle crosstalk during liver fibrosis. Hepatology 2024; 79:482-501. [PMID: 36626634 DOI: 10.1097/hep.0000000000000012] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Accepted: 10/03/2022] [Indexed: 01/12/2023]
Abstract
The synchronous functioning and quality control of organelles ensure cell survival and function and are essential for maintaining homeostasis. Prolonged exposure to stressors (viruses, bacteria, parasitic infections, alcohol, drugs) or genetic mutations often disrupt the functional integrity of organelles which plays a critical role in the initiation and progression of several diseases including chronic liver diseases. One of the most important pathologic consequences of chronic liver diseases is liver fibrosis, characterized by tissue scarring due to the progressive accumulation of extracellular matrix components. Left untreated, fibrosis may advance to life-threatening complications such as cirrhosis, hepatic decompensation, and HCC, which collectively accounts for ∼1 million deaths per year worldwide. Owing to the lack of treatment options that can regress or reverse cirrhosis, liver transplantation is currently the only available treatment for end-stage liver disease. However, the limited supply of usable donor organs, adverse effects of lifelong immunosuppressive regimes, and financial considerations pose major challenges and limit its application. Hence, effective therapeutic strategies are urgently needed. An improved understanding of the organelle-level regulation of fibrosis can help devise effective antifibrotic therapies focused on reducing organelle stress, limiting organelle damage, improving interorganelle crosstalk, and restoring organelle homeostasis; and could be a potential clinical option to avoid transplantation. This review provides a timely update on the recent findings and mechanisms covering organelle-specific dysfunctions in liver fibrosis, highlights how correction of organelle functions opens new treatment avenues and discusses the potential challenges to clinical application.
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Affiliation(s)
- Saloni Sinha
- Division of Gastroenterology and Hepatology, Department of Medicine, Weill Cornell Medicine, New York, New York, USA
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9
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Abarikwu SO, Mgbudom-Okah CJ, Ndufeiya-Kumasi LC, Monye VE, Aruoren O, Ezim OE, Omeodu SI, Charles IA. Influence of triazines and lipopolysaccharide coexposure on inflammatory response and histopathological changes in the testis and liver of BalB/c mice. Heliyon 2024; 10:e24431. [PMID: 38293467 PMCID: PMC10826326 DOI: 10.1016/j.heliyon.2024.e24431] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Revised: 01/08/2024] [Accepted: 01/09/2024] [Indexed: 02/01/2024] Open
Abstract
Background Triazines are environmental active chemicals that have been reported to alter the inflammatory status of the gonads. We tested the anti-inflammatory effect of the triazines (atrazine; ATZ, simazine; SMZ and cyanazine; CYZ) on the testis and compared it with the more classical liver model that has substantial populations of resident macrophages comparable to the testis. Methods BalB/c mice were treated with 25 mg/kg ATZ, SMZ and CYZ for 30 days and injected with lipopolysaccharide (0.5 mg/kg i.p.) 6 h before sacrifice. Myeloperoxidase activity and nitric oxide level in the testis and liver homogenates were determined by spectrophotometry whereas tumor necrosis factor-alpha and interleukin-6 concentrations were evaluated by immunoassay. Haematoxylin and eosin stained sections of the tissues were observed using a light microscope. Results Myeloperoxidase activity, nitric oxide, tumor necrosis factor-alpha, and interleukin-6 levels were decreased in the liver and testis of the triazines co-treated animals. SMZ has the most potent inhibitory effect and ATZ the least effect on inflammatory mediators in both tissues. Microscopic evaluation showed loss of inflammatory cells in the inter-tubular areas of the testis and few patchy masses of infiltrating inflammatory cells around the central vein of the liver. Conclusion Triazines inhibit the levels of inflammatory mediators in the testis and liver of mice. The anti-inflammatory effect of triazines in a lipopolysaccharide-induced inflammation model was established in this study.
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Affiliation(s)
- Sunny O. Abarikwu
- Department of Biochemistry, University of Port Harcourt, Choba, Nigeria
| | | | | | - Vivian E. Monye
- Department of Biochemistry, University of Port Harcourt, Choba, Nigeria
| | - Oke Aruoren
- Department of Biochemistry, University of Port Harcourt, Choba, Nigeria
| | - Ogechukwu E. Ezim
- Department of Biochemistry, University of Port Harcourt, Choba, Nigeria
| | - Stephen I. Omeodu
- Department of Biochemistry, University of Port Harcourt, Choba, Nigeria
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10
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Chen J, Chan TTH, Zhou J. Lipid metabolism in the immune niche of tumor-prone liver microenvironment. J Leukoc Biol 2024; 115:68-84. [PMID: 37474318 DOI: 10.1093/jleuko/qiad081] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2023] [Revised: 06/23/2023] [Accepted: 07/06/2023] [Indexed: 07/22/2023] Open
Abstract
The liver is a common primary site not only for tumorigenesis, but also for cancer metastasis. Advanced cancer patients with liver metastases also show reduced response rates and survival benefits when treated with immune checkpoint inhibitors. Accumulating evidence has highlighted the importance of the liver immune microenvironment in determining tumorigenesis, metastasis-organotropism, and immunotherapy resistance. Various immune cells such as T cells, natural killer and natural killer T cells, macrophages and dendritic cells, and stromal cells including liver sinusoidal endothelial cells, Kupffer cells, hepatic stellate cells, and hepatocytes are implicated in contributing to the immune niche of tumor-prone liver microenvironment. In parallel, as the major organ for lipid metabolism, the increased abundance of lipids and their metabolites is linked to processes crucial for nonalcoholic fatty liver disease and related liver cancer development. Furthermore, the proliferation, differentiation, and functions of hepatic immune and stromal cells are also reported to be regulated by lipid metabolism. Therefore, targeting lipid metabolism may hold great potential to reprogram the immunosuppressive liver microenvironment and synergistically enhance the immunotherapy efficacy in the circumstance of liver metastasis. In this review, we describe how the hepatic microenvironment adapts to the lipid metabolic alterations in pathologic conditions like nonalcoholic fatty liver disease. We also illustrate how these immunometabolic alterations promote the development of liver cancers and immunotherapy resistance. Finally, we discuss the current therapeutic options and hypothetic combination immunotherapies for the treatment of advanced liver cancers.
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Affiliation(s)
- Jintian Chen
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong 999077, SAR, P.R. China
| | - Thomas T H Chan
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong 999077, SAR, P.R. China
| | - Jingying Zhou
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong 999077, SAR, P.R. China
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11
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Szafranska K, Sørensen KK, Lalor PF, McCourt P. Sinusoidal cells and liver immunology. SINUSOIDAL CELLS IN LIVER DISEASES 2024:53-75. [DOI: 10.1016/b978-0-323-95262-0.00003-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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12
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Hu Y, Wang R, An N, Li C, Wang Q, Cao Y, Li C, Liu J, Wang Y. Unveiling the power of microenvironment in liver regeneration: an in-depth overview. Front Genet 2023; 14:1332190. [PMID: 38152656 PMCID: PMC10751322 DOI: 10.3389/fgene.2023.1332190] [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: 11/02/2023] [Accepted: 11/29/2023] [Indexed: 12/29/2023] Open
Abstract
The liver serves as a vital regulatory hub for various physiological processes, including sugar, protein, and fat metabolism, coagulation regulation, immune system maintenance, hormone inactivation, urea metabolism, and water-electrolyte acid-base balance control. These functions rely on coordinated communication among different liver cell types, particularly within the liver's fundamental hepatic lobular structure. In the early stages of liver development, diverse liver cells differentiate from stem cells in a carefully orchestrated manner. Despite its susceptibility to damage, the liver possesses a remarkable regenerative capacity, with the hepatic lobule serving as a secure environment for cell division and proliferation during liver regeneration. This regenerative process depends on a complex microenvironment, involving liver resident cells, circulating cells, secreted cytokines, extracellular matrix, and biological forces. While hepatocytes proliferate under varying injury conditions, their sources may vary. It is well-established that hepatocytes with regenerative potential are distributed throughout the hepatic lobules. However, a comprehensive spatiotemporal model of liver regeneration remains elusive, despite recent advancements in genomics, lineage tracing, and microscopic imaging. This review summarizes the spatial distribution of cell gene expression within the regenerative microenvironment and its impact on liver regeneration patterns. It offers valuable insights into understanding the complex process of liver regeneration.
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Affiliation(s)
- Yuelei Hu
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Jilin University, Changchun, China
- Hepato-Pancreato-Biliary Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China
| | - Ruilin Wang
- Department of Cadre’s Wards Ultrasound Diagnostics, Ultrasound Diagnostic Center, The First Hospital of Jilin University, Jilin University, Changchun, China
| | - Ni An
- Clinical Translational Science Center, Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing, China
| | - Chen Li
- Hepato-Pancreato-Biliary Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China
- College of Life Science and Bioengineering, Faculty of Environmental and Life Sciences, Beijing University of Technology, Beijing, China
| | - Qi Wang
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Jilin University, Changchun, China
- Hepato-Pancreato-Biliary Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China
| | - Yannan Cao
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Jilin University, Changchun, China
- Hepato-Pancreato-Biliary Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China
| | - Chao Li
- Hepato-Pancreato-Biliary Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China
| | - Juan Liu
- Hepato-Pancreato-Biliary Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China
| | - Yunfang Wang
- Hepato-Pancreato-Biliary Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China
- Clinical Translational Science Center, Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing, China
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13
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Zhang HR, Li YP, Shi ZJ, Liang QQ, Chen SY, You YP, Yuan T, Xu R, Xu LH, Ouyang DY, Zha QB, He XH. Triptolide induces PANoptosis in macrophages and causes organ injury in mice. Apoptosis 2023; 28:1646-1665. [PMID: 37702860 DOI: 10.1007/s10495-023-01886-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/21/2023] [Indexed: 09/14/2023]
Abstract
Macrophages represent the first lines of innate defense against pathogenic infections and are poised to undergo multiple forms of regulated cell death (RCD) upon infections or toxic stimuli, leading to multiple organ injury. Triptolide, an active compound isolated from Tripterygium wilfordii Hook F., possesses various pharmacological activities including anti-tumor and anti-inflammatory effects, but its applications have been hampered by toxic adverse effects. It remains unknown whether and how triptolide induces different forms of RCD in macrophages. In this study, we showed that triptolide exhibited significant cytotoxicity on cultured macrophages in vitro, which was associated with multiple forms of lytic cell death that could not be fully suppressed by any one specific inhibitor for a single form of RCD. Consistently, triptolide induced the simultaneous activation of pyroptotic, apoptotic and necroptotic hallmarks, which was accompanied by the co-localization of ASC specks respectively with RIPK3 or caspase-8 as well as their interaction with each other, indicating the formation of PANoptosome and thus the induction of PANoptosis. Triptolide-induced PANoptosis was associated with mitochondrial dysfunction and ROS production. PANoptosis was also induced by triptolide in mouse peritoneal macrophages in vivo. Furthermore, triptolide caused kidney and liver injury, which was associated with systemic inflammatory responses and the activation of hallmarks for PANoptosis in vivo. Collectively, our data reveal that triptolide induces PANoptosis in macrophages in vitro and exhibits nephrotoxicity and hepatotoxicity associated with induction of PANoptosis in vivo, suggesting a new avenue to alleviate triptolide's toxicity by harnessing PANoptosis.
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Affiliation(s)
- Hong-Rui Zhang
- Department of Immunobiology, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China
- Department of Clinical Laboratory, The Fifth Affiliated Hospital of Jinan University, Heyuan, 517000, China
| | - Ya-Ping Li
- Department of Immunobiology, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China
| | - Zi-Jian Shi
- Department of Fetal Medicine, The First Affiliated Hospital of Jinan University, Guangzhou, 510630, China
| | - Qi-Qi Liang
- Department of Immunobiology, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China
| | - Si-Yuan Chen
- Department of Immunobiology, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China
| | - Yi-Ping You
- Department of Immunobiology, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China
| | - Tao Yuan
- Department of Immunobiology, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China
| | - Rong Xu
- Department of Immunobiology, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China
| | - Li-Hui Xu
- Department of Cell Biology, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China
| | - Dong-Yun Ouyang
- Department of Immunobiology, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China.
| | - Qing-Bing Zha
- Department of Fetal Medicine, The First Affiliated Hospital of Jinan University, Guangzhou, 510630, China.
- Department of Clinical Laboratory, The Fifth Affiliated Hospital of Jinan University, Heyuan, 517000, China.
| | - Xian-Hui He
- Department of Immunobiology, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China.
- Department of Clinical Laboratory, The Fifth Affiliated Hospital of Jinan University, Heyuan, 517000, China.
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14
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Kholodenko IV, Yarygin KN. Hepatic Macrophages as Targets for the MSC-Based Cell Therapy in Non-Alcoholic Steatohepatitis. Biomedicines 2023; 11:3056. [PMID: 38002056 PMCID: PMC10669188 DOI: 10.3390/biomedicines11113056] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2023] [Revised: 11/02/2023] [Accepted: 11/03/2023] [Indexed: 11/26/2023] Open
Abstract
Non-alcoholic steatohepatitis (NASH) is a serious public health issue associated with the obesity pandemic. Obesity is the main risk factor for the non-alcoholic fatty liver disease (NAFLD), which progresses to NASH and then to end-stage liver disease. Currently, there are no specific pharmacotherapies of NAFLD/NASH approved by the FDA or other national regulatory bodies and the treatment includes lifestyle adjustment and medicines for improving lipid metabolism, enhancing sensitivity to insulin, balancing oxidation, and counteracting fibrosis. Accordingly, further basic research and development of new therapeutic approaches are greatly needed. Mesenchymal stem cells (MSCs) and MSC-derived extracellular vesicles prevent induced hepatocyte death in vitro and attenuate NASH symptoms in animal models of the disease. They interact with hepatocytes directly, but also target other liver cells, including Kupffer cells and macrophages recruited from the blood flow. This review provides an update on the pathogenesis of NAFLD/NASH and the key role of macrophages in the development of the disease. We examine in detail the mechanisms of the cross-talk between the MSCs and the macrophages, which are likely to be among the key targets of MSCs and their derivatives in the course of NAFLD/NASH cell therapy.
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Affiliation(s)
- Irina V. Kholodenko
- Laboratory of Cell Biology, Orekhovich Institute of Biomedical Chemistry, 119121 Moscow, Russia;
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15
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Chihara K, Okada K, Uchida F, Miura I, Komine S, Warabi E, Takayama T, Suzuki H, Matsuzaka T, Ishibashi-Kanno N, Yamagata K, Yanagawa T, Bukawa H, Shoda J. Macrophage specific restoration of the Nrf2 gene in whole-body knockout mice ameliorates steatohepatitis induced by lipopolysaccharide from Porphyromonas gingivalis through enhanced hepatic clearance. PLoS One 2023; 18:e0291880. [PMID: 37862331 PMCID: PMC10588835 DOI: 10.1371/journal.pone.0291880] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2023] [Accepted: 09/06/2023] [Indexed: 10/22/2023] Open
Abstract
Lipopolysaccharide (LPS) derived from Porphyromonas gingivalis (P.g.), which causes periodontal disease, contributes to the development of non-alcoholic steatohepatitis (NASH). We investigated the role of Nrf2, an antioxidative stress sensor, in macrophages in the development of NASH induced by LPS from P.g. We generated macrophage-specific Nrf2 gene rescue mice (Nrf2-mRes), which express Nrf2 only in macrophages, using the cre/loxp system. Wild-type (WT) mice, whole body Nrf2-knockout (Nrf2-KO) mice, and Nrf2-mRes mice were fed a high-fat diet for 18 weeks, and LPS from P.g. was administered intraperitoneally for the last 6 weeks. Nrf2-KO mice developed severe steatohepatitis with liver inflammation and fibrosis compared with WT mice, and steatohepatitis was ameliorated in Nrf2-mRes mice. The mRNA expressions of Toll-like receptor (Tlr)-2, which activates inflammatory signaling pathways after LPS binding, and α-smooth muscle actin (αSma), which promotes hepatic fibrosis, were reduced in Nrf2-mRes mice compared with Nrf2-KO mice. The protein levels of LPS-binding protein in livers were increased in Nrf2-KO mice compared with WT mice; however, the levels were reduced in Nrf2-mRes mice despite similar numbers of F4/80 positive cells, which reflect macrophage/Kupffer cell infiltration into the livers. Nrf2 in macrophages ameliorates NASH through the increased hepatic clearance of LPS.
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Affiliation(s)
- Kanako Chihara
- Department of Oral and Maxillofacial Surgery, Institute of Medicine, University of Tsukuba, Tsukuba-shi, Ibaraki, Japan
- Doctoral Program in Medical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba-shi, Ibaraki, Japan
| | - Kosuke Okada
- Division of Medical Sciences, Institute of Medicine, University of Tsukuba, Tsukuba-shi, Ibaraki, Japan
- Department of Gastroenterology, Institute of Medicine, University of Tsukuba, Tsukuba-shi, Ibaraki, Japan
| | - Fumihiko Uchida
- Department of Oral and Maxillofacial Surgery, Institute of Medicine, University of Tsukuba, Tsukuba-shi, Ibaraki, Japan
| | - Ikuru Miura
- Faculty of Sports and Health Science, Fukuoka University, Fukuoka-shi, Fukuoka, Japan
| | - Shoichi Komine
- Department of Acupuncture and Moxibustion, Faculty of Human Care, Teikyo Heisei University, Toshima-ku, Tokyo, Japan
| | - Eiji Warabi
- Division of Biomedical Sciences, Institute of Medicine, University of Tsukuba, Tsukuba-shi, Ibaraki, Japan
| | - Takako Takayama
- Department of Gastroenterology, Institute of Medicine, University of Tsukuba, Tsukuba-shi, Ibaraki, Japan
| | - Hideo Suzuki
- Department of Gastroenterology, Institute of Medicine, University of Tsukuba, Tsukuba-shi, Ibaraki, Japan
| | - Takashi Matsuzaka
- Transborder Medical Research Center, University of Tsukuba, Tsukuba-shi, Ibaraki, Japan
| | - Naomi Ishibashi-Kanno
- Department of Oral and Maxillofacial Surgery, Institute of Medicine, University of Tsukuba, Tsukuba-shi, Ibaraki, Japan
| | - Kenji Yamagata
- Department of Oral and Maxillofacial Surgery, Institute of Medicine, University of Tsukuba, Tsukuba-shi, Ibaraki, Japan
| | - Toru Yanagawa
- Department of Oral and Maxillofacial Surgery, Institute of Medicine, University of Tsukuba, Tsukuba-shi, Ibaraki, Japan
| | - Hiroki Bukawa
- Department of Oral and Maxillofacial Surgery, Institute of Medicine, University of Tsukuba, Tsukuba-shi, Ibaraki, Japan
| | - Junichi Shoda
- Division of Medical Sciences, Institute of Medicine, University of Tsukuba, Tsukuba-shi, Ibaraki, Japan
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16
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Kang HJ, Lee JM, Kim SW. Sonazoid-enhanced ultrasonography for noninvasive imaging diagnosis of hepatocellular carcinoma: special emphasis on the 2022 KLCA-NCC guideline. Ultrasonography 2023; 42:479-489. [PMID: 37423603 PMCID: PMC10555687 DOI: 10.14366/usg.23051] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Revised: 06/02/2023] [Accepted: 06/09/2023] [Indexed: 07/11/2023] Open
Abstract
Contrast-enhanced ultrasonography (CEUS) is a noninvasive imaging modality used to diagnose hepatocellular carcinoma (HCC) based on specific imaging features, without the need for pathologic confirmation. Two types of ultrasound contrast agents are commercially available: pure intravascular agents (such as SonoVue) and Kupffer agents (such as Sonazoid). Major guidelines recognize CEUS as a reliable imaging method for HCC diagnosis, although they differ depending on the contrast agents used. The Korean Liver Cancer Association-National Cancer Center guideline includes CEUS with either SonoVue or Sonazoid as a second-line diagnostic technique. However, Sonazoid-enhanced ultrasound is associated with several unresolved issues. This review provides a comparative overview of these contrast agents regarding pharmacokinetic features, examination protocols, diagnostic criteria for HCC, and potential applications in the HCC diagnostic algorithm.
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Affiliation(s)
- Hyo-Jin Kang
- Department of Radiology, Seoul National University Hospital, Seoul, Korea
- Department of Radiology, Seoul National University College of Medicine, Seoul, Korea
| | - Jeong Min Lee
- Department of Radiology, Seoul National University Hospital, Seoul, Korea
- Department of Radiology, Seoul National University College of Medicine, Seoul, Korea
- Institute of Radiation Medicine, Seoul National University Medical Research Center, Seoul, Korea
| | - Se Woo Kim
- Department of Radiology, Armed Forces Daejeon Hospital, Daejeon, Korea
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17
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Hassan GS, Flores Molina M, Shoukry NH. The multifaceted role of macrophages during acute liver injury. Front Immunol 2023; 14:1237042. [PMID: 37736102 PMCID: PMC10510203 DOI: 10.3389/fimmu.2023.1237042] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Accepted: 08/15/2023] [Indexed: 09/23/2023] Open
Abstract
The liver is situated at the interface of the gut and circulation where it acts as a filter for blood-borne and gut-derived microbes and biological molecules, promoting tolerance of non-invasive antigens while driving immune responses against pathogenic ones. Liver resident immune cells such as Kupffer cells (KCs), a subset of macrophages, maintain homeostasis under physiological conditions. However, upon liver injury, these cells and others recruited from circulation participate in the response to injury and the repair of tissue damage. Such response is thus spatially and temporally regulated and implicates interconnected cells of immune and non-immune nature. This review will describe the hepatic immune environment during acute liver injury and the subsequent wound healing process. In its early stages, the wound healing immune response involves a necroinflammatory process characterized by partial depletion of resident KCs and lymphocytes and a significant infiltration of myeloid cells including monocyte-derived macrophages (MoMFs) complemented by a wave of pro-inflammatory mediators. The subsequent repair stage includes restoring KCs, initiating angiogenesis, renewing extracellular matrix and enhancing proliferation/activation of resident parenchymal and mesenchymal cells. This review will focus on the multifaceted role of hepatic macrophages, including KCs and MoMFs, and their spatial distribution and roles during acute liver injury.
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Affiliation(s)
- Ghada S. Hassan
- Centre de Recherche du Centre hospitalier de l’Université de Montréal (CRCHUM), Montréal, QC, Canada
| | - Manuel Flores Molina
- Centre de Recherche du Centre hospitalier de l’Université de Montréal (CRCHUM), Montréal, QC, Canada
- Département de microbiologie, infectiologie et immunologie, Faculté de médecine, Université de Montréal, Montréal, QC, Canada
| | - Naglaa H. Shoukry
- Centre de Recherche du Centre hospitalier de l’Université de Montréal (CRCHUM), Montréal, QC, Canada
- Département de médecine, Faculté de médecine, Université de Montréal, Montréal, QC, Canada
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18
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Blake MJ, Steer CJ. Liver Regeneration in Acute on Chronic Liver Failure. Clin Liver Dis 2023; 27:595-616. [PMID: 37380285 DOI: 10.1016/j.cld.2023.03.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/30/2023]
Abstract
Liver regeneration is a multifaceted process by which the organ regains its original size and histologic organization. In recent decades, substantial advances have been made in our understanding of the mechanisms underlying regeneration following loss of hepatic mass. Liver regeneration in acute liver failure possesses several classic pathways, while also exhibiting unique differences in key processes such as the roles of differentiated cells and stem cell analogs. Here we summarize these unique differences and new molecular mechanisms involving the gut-liver axis, immunomodulation, and microRNAs with an emphasis on applications to the patient population through stem cell therapies and prognostication.
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Affiliation(s)
- Madelyn J Blake
- Department of Medicine, University of Minnesota Medical School, 420 Delaware Street Southeast, MMC 36, Minneapolis, MN 55455, USA.
| | - Clifford J Steer
- Department of Medicine, University of Minnesota Medical School, 420 Delaware Street Southeast, MMC 36, Minneapolis, MN 55455, USA; Department of Genetics, Cell Biology and Development, University of Minnesota Medical School, 420 Delaware Street Southeast, MMC 36, Minneapolis, MN 55455, USA
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19
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Dart SJ, Prosser AC, Huang WH, Liu L, Lucas AD, Delriviere L, Gaudieri S, Jeffrey GP, Lucas M. Subset-specific Retention of Donor Myeloid Cells After Major Histocompatibility Complex-matched and Mismatched Liver Transplantation. Transplantation 2023; 107:1502-1512. [PMID: 36584373 PMCID: PMC10508270 DOI: 10.1097/tp.0000000000004481] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2022] [Revised: 10/14/2022] [Accepted: 11/03/2022] [Indexed: 12/31/2022]
Abstract
BACKGROUND During solid organ transplantation, donor leukocytes, including myeloid cells, are transferred within the organ to the recipient. Both tolerogenic and alloreactive roles have been attributed to donor myeloid cells; however, their subset-specific retention posttransplantation has not been investigated in detail. METHODS Major histocompatibility complex (MHC)-matched and mismatched liver transplants were performed in mice, and the fate of donor and recipient myeloid cells was assessed. RESULTS Following MHC-matched transplantation, a proportion of donor myeloid cells was retained in the graft, whereas others egressed and persisted in the blood, spleen, and bone marrow but not the lymph nodes. In contrast, after MHC-mismatched transplantation, all donor myeloid cells, except Kupffer cells, were depleted. This depletion was caused by recipient T and B cells because all donor myeloid subsets were retained in MHC-mismatched grafts when recipients lacked T and B cells. Recipient myeloid cells rapidly infiltrated MHC-matched and, to a greater extent, MHC-mismatched liver grafts. MHC-mismatched grafts underwent a transient rejection episode on day 7, coinciding with a transition in macrophages to a regulatory phenotype, after which rejection resolved. CONCLUSIONS Phenotypic and kinetic differences in the myeloid cell responses between MHC-matched and mismatched grafts were identified. A detailed understanding of the dynamics of immune responses to transplantation is critical to improving graft outcomes.
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Affiliation(s)
- Sarah J. Dart
- Medical School, The University of Western Australia, Perth, WA, Australia
| | - Amy C. Prosser
- Medical School, The University of Western Australia, Perth, WA, Australia
| | - Wen Hua Huang
- Medical School, The University of Western Australia, Perth, WA, Australia
- Western Australian Liver Transplant Service, Sir Charles Gairdner Hospital, Perth, WA, Australia
| | - Liu Liu
- Medical School, The University of Western Australia, Perth, WA, Australia
| | - Andrew D. Lucas
- School of Biomedical Sciences, The University of Western Australia, Perth, WA, Australia
| | - Luc Delriviere
- Medical School, The University of Western Australia, Perth, WA, Australia
- Western Australian Liver Transplant Service, Sir Charles Gairdner Hospital, Perth, WA, Australia
| | - Silvana Gaudieri
- School of Human Sciences, The University of Western Australia, Perth, WA, Australia
| | - Gary P. Jeffrey
- Medical School, The University of Western Australia, Perth, WA, Australia
- Western Australian Liver Transplant Service, Sir Charles Gairdner Hospital, Perth, WA, Australia
- Department of Hepatology, Sir Charles Gairdner Hospital, Perth, WA, Australia
| | - Michaela Lucas
- Medical School, The University of Western Australia, Perth, WA, Australia
- Department of Immunology, Sir Charles Gairdner Hospital and PathWest Laboratory Medicine, Perth, WA, Australia
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20
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Lazarov T, Juarez-Carreño S, Cox N, Geissmann F. Physiology and diseases of tissue-resident macrophages. Nature 2023; 618:698-707. [PMID: 37344646 PMCID: PMC10649266 DOI: 10.1038/s41586-023-06002-x] [Citation(s) in RCA: 135] [Impact Index Per Article: 67.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2021] [Accepted: 03/23/2023] [Indexed: 06/23/2023]
Abstract
Embryo-derived tissue-resident macrophages are the first representatives of the haematopoietic lineage to emerge in metazoans. In mammals, resident macrophages originate from early yolk sac progenitors and are specified into tissue-specific subsets during organogenesis-establishing stable spatial and functional relationships with specialized tissue cells-and persist in adults. Resident macrophages are an integral part of tissues together with specialized cells: for instance, microglia reside with neurons in brain, osteoclasts reside with osteoblasts in bone, and fat-associated macrophages reside with white adipocytes in adipose tissue. This ancillary cell type, which is developmentally and functionally distinct from haematopoietic stem cell and monocyte-derived macrophages, senses and integrates local and systemic information to provide specialized tissue cells with the growth factors, nutrient recycling and waste removal that are critical for tissue growth, homeostasis and repair. Resident macrophages contribute to organogenesis, promote tissue regeneration following damage and contribute to tissue metabolism and defence against infectious disease. A correlate is that genetic or environment-driven resident macrophage dysfunction is a cause of degenerative, metabolic and possibly inflammatory and tumoural diseases. In this Review, we aim to provide a conceptual outline of our current understanding of macrophage physiology and its importance in human diseases, which may inform and serve the design of future studies.
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Affiliation(s)
- Tomi Lazarov
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School of Medical Sciences, New York, NY, USA
| | - Sergio Juarez-Carreño
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Nehemiah Cox
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Frederic Geissmann
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
- Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School of Medical Sciences, New York, NY, USA.
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21
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Pant R, Kabeer SW, Sharma S, Kumar V, Patra D, Pal D, Tikoo K. Pharmacological inhibition of DNMT1 restores macrophage autophagy and M2 polarization in western diet-induced Nonalcoholic fatty liver disease. J Biol Chem 2023:104779. [PMID: 37142224 DOI: 10.1016/j.jbc.2023.104779] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Revised: 04/16/2023] [Accepted: 04/17/2023] [Indexed: 05/06/2023] Open
Abstract
Non-Alcoholic Fatty Liver Disease (NAFLD) is associated with an increased ratio of classically activated M1 macrophages/Kupffer cells to alternatively activated M2 macrophages, which plays an imperative role in the development & progression of NAFLD. However, little is known about the precise mechanism behind macrophage polarization shift. Here, we provide evidence regarding the relationship between the polarization shift in Kupffer cells and autophagy resulting from lipid exposure. High-fat and High-fructose diet supplementation for 10 weeks significantly increased the abundance of Kupffer cells with an M1-predominant phenotype in mice. Interestingly, at the molecular level, we also observed a concomitant increase in expression of DNA methyltransferases DNMT1 and reduced autophagy in the NAFLD mice. We also observed hypermethylation at the promotor regions of autophagy genes (LC3B, ATG-5, and ATG-7). Furthermore, the pharmacological inhibition of DNMT1 by using DNA hypomethylating agents (Azacitidine and Zebularine) restored Kupffer cell autophagy, M1/M2 polarization and therefore prevented the progression of NAFLD. We report the presence of a link between epigenetic regulation of autophagy gene and macrophage polarization switch. We provide the evidence that epigenetic modulators restore the lipid-induced imbalance in macrophage polarization, therefore, preventing the development & progression of NAFLD.
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Affiliation(s)
- Rajat Pant
- Laboratory of Epigenetics and Diseases, Department of Pharmacology and Toxicology National Institute of Pharmaceutical Education and Research, S.A.S Nagar (Mohali), Punjab- 160062, India
| | - Shaheen Wasil Kabeer
- Laboratory of Epigenetics and Diseases, Department of Pharmacology and Toxicology National Institute of Pharmaceutical Education and Research, S.A.S Nagar (Mohali), Punjab- 160062, India
| | - Shivam Sharma
- Laboratory of Epigenetics and Diseases, Department of Pharmacology and Toxicology National Institute of Pharmaceutical Education and Research, S.A.S Nagar (Mohali), Punjab- 160062, India
| | - Vinod Kumar
- Laboratory of Epigenetics and Diseases, Department of Pharmacology and Toxicology National Institute of Pharmaceutical Education and Research, S.A.S Nagar (Mohali), Punjab- 160062, India
| | - Debarun Patra
- Department for Biomedical Engineering, Indian Institute of Technology Ropar, Rupnagar -140001, Punjab, India
| | - Durba Pal
- Department for Biomedical Engineering, Indian Institute of Technology Ropar, Rupnagar -140001, Punjab, India
| | - Kulbhushan Tikoo
- Laboratory of Epigenetics and Diseases, Department of Pharmacology and Toxicology National Institute of Pharmaceutical Education and Research, S.A.S Nagar (Mohali), Punjab- 160062, India.
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22
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Kotlyarov S. Immune and metabolic cross-links in the pathogenesis of comorbid non-alcoholic fatty liver disease. World J Gastroenterol 2023; 29:597-615. [PMID: 36742172 PMCID: PMC9896611 DOI: 10.3748/wjg.v29.i4.597] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Revised: 10/28/2022] [Accepted: 11/10/2022] [Indexed: 01/20/2023] Open
Abstract
In recent years, there has been a steady growth of interest in non-alcoholic fatty liver disease (NAFLD), which is associated with negative epidemiological data on the prevalence of the disease and its clinical significance. NAFLD is closely related to the metabolic syndrome and these relationships are the subject of active research. A growing body of evidence shows cross-linkages between metabolic abnormalities and the innate immune system in the development and progression of NAFLD. These links are bidirectional and largely still unclear, but a better understanding of them will improve the quality of diagnosis and management of patients. In addition, lipid metabolic disorders and the innate immune system link NAFLD with other diseases, such as atherosclerosis, which is of great clinical importance.
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Affiliation(s)
- Stanislav Kotlyarov
- Department of Nursing, Ryazan State Medical University, Ryazan 390026, Russia
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23
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Xiao Z, Liu M, Yang F, Liu G, Liu J, Zhao W, Ma S, Duan Z. Programmed cell death and lipid metabolism of macrophages in NAFLD. Front Immunol 2023; 14:1118449. [PMID: 36742318 PMCID: PMC9889867 DOI: 10.3389/fimmu.2023.1118449] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Accepted: 01/06/2023] [Indexed: 01/19/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) has now become the leading chronic liver disease worldwide with lifestyle changes. This may lead to NAFLD becoming the leading cause of end-stage liver disease in the future. To date, there are still no effective therapeutic drugs for NAFLD. An in-depth exploration of the pathogenesis of NAFLD can help to provide a basis for new therapeutic agents or strategies. As the most important immune cells of the liver, macrophages play an important role in the occurrence and development of liver inflammation and are expected to become effective targets for NAFLD treatment. Programmed cell death (PCD) of macrophages plays a regulatory role in phenotypic transformation, and there is also a certain connection between different types of PCD. However, how PCD regulates macrophage polarization has still not been systematically elucidated. Based on the role of lipid metabolic reprogramming in macrophage polarization, PCD may alter the phenotype by regulating lipid metabolism. We reviewed the effects of macrophages on inflammation in NAFLD and changes in their lipid metabolism, as well as the relationship between different types of PCD and lipid metabolism in macrophages. Furthermore, interactions between different types of PCD and potential therapeutic agents targeting of macrophages PCD are also explored.
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Affiliation(s)
- Zhun Xiao
- Department of Digestive Diseases, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, China
| | - Minghao Liu
- Department of Digestive Diseases, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, China
| | - Fangming Yang
- Department of Digestive Diseases, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, China
| | - Guangwei Liu
- Department of Digestive Diseases, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, China
| | - Jiangkai Liu
- Department of Digestive Diseases, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, China
| | - Wenxia Zhao
- Department of Digestive Diseases, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, China
| | - Suping Ma
- Department of Digestive Diseases, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, China,*Correspondence: Suping Ma, ; Zhongping Duan,
| | - Zhongping Duan
- Beijing Institute of Hepatology, Beijing Youan Hospital Capital Medical University, Beijing, China,*Correspondence: Suping Ma, ; Zhongping Duan,
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Research and Application of Kupffer Cell Thresholds for BSA Nanoparticles. MOLECULES (BASEL, SWITZERLAND) 2023; 28:molecules28020880. [PMID: 36677939 PMCID: PMC9864197 DOI: 10.3390/molecules28020880] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/04/2022] [Revised: 12/29/2022] [Accepted: 01/06/2023] [Indexed: 01/18/2023]
Abstract
Over the past decade, the dose of nanoparticles given to solid tumors has remained at a median of 0.7% of the injected dose. Most nanoparticles are trapped in a mononuclear phagocyte system (MPS), of which 85% are Kupffer cells. In our study, threshold doses of bovine serum albumin (BSA) nanoparticles were investigated for the uptake of Kupffer cells in vitro and in vivo. The antitumor effect and safety of albumin-bound paclitaxel (ABP) were improved by using threshold doses of BSA nanoparticles. We found a threshold dose of 20,000 nanoparticles per macrophage uptake in vitro and a saturation dose of 0.3 trillion nanoparticles in tumor-bearing mice. In vivo efficacy and safety evaluations demonstrated that the threshold doses of blank BSA nanoparticles could significantly improve the efficacy and safety of ABP against tumors compared with ABP alone. In this study, the delivery efficiency of ABP was improved by using blank nanoparticles to saturate Kupffer cells, which provided a new approach to studying the Kupffer cell saturation threshold and thus a new scheme for improving the curative effect of ABP.
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25
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Wang Z, Chen C, Su Y, Ke N. Function and characteristics of TIM‑4 in immune regulation and disease (Review). Int J Mol Med 2022; 51:10. [PMID: 36524355 PMCID: PMC9848438 DOI: 10.3892/ijmm.2022.5213] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Accepted: 11/23/2022] [Indexed: 12/14/2022] Open
Abstract
T‑cell/transmembrane immunoglobulin and mucin domain containing 4 (TIM‑4) is a phosphatidylserine receptor that is mainly expressed on antigen‑presenting cells and is involved in the recognition and efferocytosis of apoptotic cells. TIM‑4 has been found to be expressed in immune cells such as natural killer T, B and mast cells and to participate in multiple aspects of immune regulation, suggesting that TIM‑4 may be involved in a variety of immune‑related diseases. Recent studies have confirmed that TIM‑4 is also abnormally expressed in a variety of malignant tumor cells and is closely associated with the occurrence and development of tumors and the tumor immune microenvironment. The present study aimed to describe the expression and functional characteristics of TIM‑4 in detail and to comprehensively discuss its role in pathophysiological processes such as infection, allergy, metabolism, autoimmunity and tumor immunity. The current review provided a comprehensive understanding of the functions and characteristics of TIM‑4, as well as novel ideas for the diagnosis and treatment of diseases.
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Affiliation(s)
- Ziyao Wang
- Department of Pancreatic Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Chen Chen
- Department of Radiology, The First People's Hospital of Chengdu, Chengdu, Sichuan 610095, P.R. China
| | - Yingzhen Su
- Kunming University School of Medicine, Kunming University School, Kunming, Yunnan 650124, P.R. China
| | - Nengwen Ke
- Department of Pancreatic Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China,Correspondence to: Professor Nengwen Ke, Department of Pancreatic Surgery, West China Hospital, Sichuan University, 37 Guoxue Lane, Chengdu, Sichuan 610041, P.R. China, E-mail:
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26
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Jiang YJ, Gao JF, Lin LH, Li H, Meng QG, Qu YF, Ji X. Single-cell transcriptomes from turtle livers reveal sensitivity of hepatic immune cells to bacteria-infection. FISH & SHELLFISH IMMUNOLOGY 2022; 131:847-854. [PMID: 36273515 DOI: 10.1016/j.fsi.2022.10.033] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/27/2022] [Revised: 10/10/2022] [Accepted: 10/17/2022] [Indexed: 06/16/2023]
Abstract
The liver is important in the synthesis, metabolism and storage of nutrients, detoxification and immune response of the body, and the liver immune response against exogenous pathogens from the intestinal tract plays a key role in the immune activities. However, the cellular composition of the liver immune atlas remains sparsely studied in reptiles. We used single-cell RNA sequencing to identify the cellular profile of the liver of the Chinese soft-shelled turtle (Pelodiscus sinensis). We obtained the transcriptional landscape based on 9938 cells from the fractionation of fresh hepatic tissues from two individuals, uninfected and infected with bacteria (Aeromonas hydrophila). We identified seven hepatic immune cell subsets, including plasma, erythroid, T/NK, B, endothelial, dendritic and Kupffer cells. Bacteria-infection altered the number of liver immune cells, as revealed by the fact that the infected turtle had more plasma, endothelial and Kupffer cells and fewer T/NK, dendritic and erythroid cells than did the uninfected turtle. Our study is the first to provide a comprehensive view of the hepatic immune landscape of P. sinensis at the single-cell resolution that outlines the characteristics of immune cells in the turtle liver and provides a liver transcriptome baseline for turtle immunology.
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Affiliation(s)
- Yi-Jin Jiang
- Jiangsu Key Laboratory for Biodiversity and Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, 210023, Jiangsu, China
| | - Jian-Fang Gao
- Hangzhou Key Laboratory for Ecosystem Protection and Restoration, College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou, 311121, Zhejiang, China
| | - Long-Hui Lin
- Hangzhou Key Laboratory for Ecosystem Protection and Restoration, College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou, 311121, Zhejiang, China
| | - Hong Li
- Jiangsu Key Laboratory for Biodiversity and Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, 210023, Jiangsu, China
| | - Qing-Guo Meng
- Jiangsu Key Laboratory for Biodiversity and Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, 210023, Jiangsu, China
| | - Yan-Fu Qu
- Jiangsu Key Laboratory for Biodiversity and Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, 210023, Jiangsu, China.
| | - Xiang Ji
- Zhejiang Provincial Key Laboratory for Water Environment and Marine Biological Resources Protection, College of Life and Environmental Sciences, Wenzhou University, Wenzhou, 325035, Zhejiang, China.
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27
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Seo HY, Lee SH, Han E, Hwang JS, Han S, Kim MK, Jang BK. Evogliptin Directly Inhibits Inflammatory and Fibrotic Signaling in Isolated Liver Cells. Int J Mol Sci 2022; 23:ijms231911636. [PMID: 36232933 PMCID: PMC9569597 DOI: 10.3390/ijms231911636] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 09/22/2022] [Accepted: 09/28/2022] [Indexed: 11/09/2022] Open
Abstract
Chronic liver inflammation can lead to fibrosis, cirrhosis, and hepatocellular carcinoma. Kupffer cells (KC) secrete proinflammatory and fibrogenic cytokines in response to lipopolysaccharide (LPS), and so play an important role in liver inflammation, where they induce hepatocellular damage. LPS also activates hepatic stellate cells and induces extracellular matrix deposition. In this study, we used isolated primary KC, primary hepatocytes, and primary hepatic stellate cells (HSC) to investigate whether evogliptin directly inhibits inflammatory and fibrotic signaling. We found that evogliptin inhibited LPS-induced secretion of inducible nitric oxide synthase and transforming growth factor β (TGF-β) from KC. Moreover, evogliptin inhibited inflammatory mediator release from hepatocytes and hepatic stellate cell activation that were induced by KC-secreted cytokines. In hepatocytes, evogliptin also inhibited LPS-induced expression of proinflammatory cytokines and fibrotic TGF-β. In addition, evogliptin inhibited TGF-β-induced increases in connective tissue growth factor levels and HSC activation. These findings indicate that evogliptin inhibits inflammatory and fibrotic signaling in liver cells. We also showed that the inhibitory effect of evogliptin on inflammatory and fibrotic signaling is associated with the induction of autophagy.
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Affiliation(s)
- Hye-Young Seo
- Department of Internal Medicine, School of Medicine, Institute for Medical Science, Keimyung University, Daegu 42601, Korea
| | - So-Hee Lee
- Department of Internal Medicine, School of Medicine, Institute for Medical Science, Keimyung University, Daegu 42601, Korea
| | - Eugene Han
- Department of Internal Medicine, School of Medicine, Institute for Medical Science, Keimyung University, Daegu 42601, Korea
| | - Jae Seok Hwang
- Department of Internal Medicine, School of Medicine, Institute for Medical Science, Keimyung University, Daegu 42601, Korea
| | - Sol Han
- Department of Physiology, University of Washington, Seattle, WA 98195, USA
| | - Mi Kyung Kim
- Department of Internal Medicine, School of Medicine, Institute for Medical Science, Keimyung University, Daegu 42601, Korea
- Correspondence: (M.K.K.); (B.K.J.); Tel.: +82-53-258-7730 (M.K.K.); +82-53-258-7720 (B.K.J.)
| | - Byoung Kuk Jang
- Department of Internal Medicine, School of Medicine, Institute for Medical Science, Keimyung University, Daegu 42601, Korea
- Correspondence: (M.K.K.); (B.K.J.); Tel.: +82-53-258-7730 (M.K.K.); +82-53-258-7720 (B.K.J.)
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28
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Paris J, Henderson NC. Liver zonation, revisited. Hepatology 2022; 76:1219-1230. [PMID: 35175659 PMCID: PMC9790419 DOI: 10.1002/hep.32408] [Citation(s) in RCA: 71] [Impact Index Per Article: 23.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Revised: 02/08/2022] [Accepted: 02/08/2022] [Indexed: 12/31/2022]
Abstract
The concept of hepatocyte functional zonation is well established, with differences in metabolism and xenobiotic processing determined by multiple factors including oxygen and nutrient levels across the hepatic lobule. However, recent advances in single-cell genomics technologies, including single-cell and nuclei RNA sequencing, and the rapidly evolving fields of spatial transcriptomic and proteomic profiling have greatly increased our understanding of liver zonation. Here we discuss how these transformative experimental strategies are being leveraged to dissect liver zonation at unprecedented resolution and how this new information should facilitate the emergence of novel precision medicine-based therapies for patients with liver disease.
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Affiliation(s)
- Jasmin Paris
- Centre for Inflammation ResearchThe Queen’s Medical Research InstituteEdinburgh BioQuarterUniversity of EdinburghEdinburghUK
| | - Neil C. Henderson
- Centre for Inflammation ResearchThe Queen’s Medical Research InstituteEdinburgh BioQuarterUniversity of EdinburghEdinburghUK
- MRC Human Genetics UnitInstitute of Genetics and CancerUniversity of EdinburghEdinburghUK
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29
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Liu N, Wang X, Steer CJ, Song G. MicroRNA-206 promotes the recruitment of CD8 + T cells by driving M1 polarisation of Kupffer cells. Gut 2022; 71:1642-1655. [PMID: 34706869 PMCID: PMC9279850 DOI: 10.1136/gutjnl-2021-324170] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Accepted: 09/02/2021] [Indexed: 01/06/2023]
Abstract
OBJECTIVE Kupffer cells (KCs) protect against hepatocellular carcinoma (HCC) by communicating with other immune cells. However, the underlying mechanism(s) of this process is incompletely understood. DESIGN FVB/NJ mice were hydrodynamically injected with AKT/Ras and Sleeping Beauty transposon to induce HCC. Mini-circle and Sleeping Beauty were used to overexpress microRNA-206 in KCs of mice. Flow cytometry and immunostaining were used to evaluate the change in the immune system. RESULTS Hydrodynamic injection of AKT/Ras into mice drove M2 polarisation of KCs and depletion of cytotoxic T cells (CTLs) and promoted HCC development. M1-to-M2 transition of KCs impaired microRNA-206 biogenesis. By targeting Klf4 (kruppel like factor 4) and, thereby, enhancing the production of M1 markers including C-C motif chemokine ligand 2 (CCL2), microRNA-206 promoted M1 polarisation of macrophages. Indeed, microRNA-206-mediated increase of CCL2 facilitated hepatic recruitment of CTLs via CCR2. Disrupting each component of the KLF4/CCL2/CCR2 axis impaired the ability of microRNA-206 to drive M1 polarisation of macrophages and recruit CTLs. In AKT/Ras mice, KC-specific expression of microRNA-206 drove M1 polarisation of KCs and hepatic recruitment of CTLs and fully prevented HCC, while 100% of control mice died from HCC. Disrupting the interaction between microRNA-206 and Klf4 in KCs and depletion of CD8+ T cells impaired the ability of miR-206 to prevent HCC. CONCLUSIONS M2 polarisation of KCs is a major contributor of HCC in AKT/Ras mice. MicroRNA-206, by driving M1 polarisation of KCs, promoted the recruitment of CD8+ T cells and prevented HCC, suggesting its potential use as an immunotherapeutic approach.
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Affiliation(s)
- Ningning Liu
- Department of Medicine, University of Minnesota Twin Cities, Minneapolis, Minnesota, USA
| | - Xiaomei Wang
- Department of Medicine, University of Minnesota Twin Cities, Minneapolis, Minnesota, USA
| | - Clifford John Steer
- Department of Medicine, University of Minnesota Twin Cities, Minneapolis, Minnesota, USA
| | - Guisheng Song
- Department of Medicine, University of Minnesota Twin Cities, Minneapolis, Minnesota, USA
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30
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Approaches to Improve Macromolecule and Nanoparticle Accumulation in the Tumor Microenvironment by the Enhanced Permeability and Retention Effect. Polymers (Basel) 2022; 14:polym14132601. [PMID: 35808648 PMCID: PMC9268820 DOI: 10.3390/polym14132601] [Citation(s) in RCA: 48] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Revised: 06/17/2022] [Accepted: 06/18/2022] [Indexed: 12/17/2022] Open
Abstract
Passive targeting is the foremost mechanism by which nanocarriers and drug-bearing macromolecules deliver their payload selectively to solid tumors. An important driver of passive targeting is the enhanced permeability and retention (EPR) effect, which is the cornerstone of most carrier-based tumor-targeted drug delivery efforts. Despite the huge number of publications showcasing successes in preclinical animal models, translation to the clinic has been poor, with only a few nano-based drugs currently being used for the treatment of cancers. Several barriers and factors have been adduced for the low delivery efficiency to solid tumors and poor clinical translation, including the characteristics of the nanocarriers and macromolecules, vascular and physiological barriers, the heterogeneity of tumor blood supply which affects the homogenous distribution of nanocarriers within tumors, and the transport and penetration depth of macromolecules and nanoparticles in the tumor matrix. To address the challenges associated with poor tumor targeting and therapeutic efficacy in humans, the identified barriers that affect the efficiency of the enhanced permeability and retention (EPR) effect for macromolecular therapeutics and nanoparticle delivery systems need to be overcome. In this review, approaches to facilitate improved EPR delivery outcomes and the clinical translation of novel macromolecular therapeutics and nanoparticle drug delivery systems are discussed.
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31
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NAFLD: Mechanisms, Treatments, and Biomarkers. Biomolecules 2022; 12:biom12060824. [PMID: 35740949 PMCID: PMC9221336 DOI: 10.3390/biom12060824] [Citation(s) in RCA: 183] [Impact Index Per Article: 61.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Revised: 05/31/2022] [Accepted: 06/02/2022] [Indexed: 02/07/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD), recently renamed metabolic-associated fatty liver disease (MAFLD), is one of the most common causes of liver diseases worldwide. NAFLD is growing in parallel with the obesity epidemic. No pharmacological treatment is available to treat NAFLD, specifically. The reason might be that NAFLD is a multi-factorial disease with an incomplete understanding of the mechanisms involved, an absence of accurate and inexpensive imaging tools, and lack of adequate non-invasive biomarkers. NAFLD consists of the accumulation of excess lipids in the liver, causing lipotoxicity that might progress to metabolic-associated steatohepatitis (NASH), liver fibrosis, and hepatocellular carcinoma. The mechanisms for the pathogenesis of NAFLD, current interventions in the management of the disease, and the role of sirtuins as potential targets for treatment are discussed here. In addition, the current diagnostic tools, and the role of non-coding RNAs as emerging diagnostic biomarkers are summarized. The availability of non-invasive biomarkers, and accurate and inexpensive non-invasive diagnosis tools are crucial in the detection of the early signs in the progression of NAFLD. This will expedite clinical trials and the validation of the emerging therapeutic treatments.
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32
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Ngo W, Ahmed S, Blackadar C, Bussin B, Ji Q, Mladjenovic SM, Sepahi Z, Chan WC. Why nanoparticles prefer liver macrophage cell uptake in vivo. Adv Drug Deliv Rev 2022; 185:114238. [PMID: 35367524 DOI: 10.1016/j.addr.2022.114238] [Citation(s) in RCA: 93] [Impact Index Per Article: 31.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Revised: 02/26/2022] [Accepted: 03/23/2022] [Indexed: 02/08/2023]
Abstract
Effective delivery of therapeutic and diagnostic nanoparticles is dependent on their ability to accumulate in diseased tissues. However, most nanoparticles end up in liver macrophages regardless of nanoparticle design after administration. In this review, we describe the interactions of liver macrophages with nanoparticles. Liver macrophages have significant advantages in interacting with circulating nanoparticles over most target cells and tissues in the body. We describe these advantages in this article. Understanding these advantages will enable the development of strategies to overcome liver macrophages and deliver nanoparticles to targeted diseased tissues effectively. Ultimately, these approaches will increase the therapeutic efficacy and diagnostic signal of nanoparticles.
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33
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Rohm TV, Meier DT, Olefsky JM, Donath MY. Inflammation in obesity, diabetes, and related disorders. Immunity 2022; 55:31-55. [PMID: 35021057 PMCID: PMC8773457 DOI: 10.1016/j.immuni.2021.12.013] [Citation(s) in RCA: 836] [Impact Index Per Article: 278.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2021] [Revised: 12/13/2021] [Accepted: 12/17/2021] [Indexed: 01/13/2023]
Abstract
Obesity leads to chronic, systemic inflammation and can lead to insulin resistance (IR), β-cell dysfunction, and ultimately type 2 diabetes (T2D). This chronic inflammatory state contributes to long-term complications of diabetes, including non-alcoholic fatty liver disease (NAFLD), retinopathy, cardiovascular disease, and nephropathy, and may underlie the association of type 2 diabetes with other conditions such as Alzheimer's disease, polycystic ovarian syndrome, gout, and rheumatoid arthritis. Here, we review the current understanding of the mechanisms underlying inflammation in obesity, T2D, and related disorders. We discuss how chronic tissue inflammation results in IR, impaired insulin secretion, glucose intolerance, and T2D and review the effect of inflammation on diabetic complications and on the relationship between T2D and other pathologies. In this context, we discuss current therapeutic options for the treatment of metabolic disease, advances in the clinic and the potential of immune-modulatory approaches.
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Affiliation(s)
- Theresa V. Rohm
- Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA
| | - Daniel T. Meier
- Clinic of Endocrinology, Diabetes and Metabolism, University Hospital Basel, CH-4031 Basel, Switzerland.,Department of Biomedicine (DBM), University of Basel, University Hospital Basel, CH-4031 Basel, Switzerland
| | - Jerrold M. Olefsky
- Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA
| | - Marc Y. Donath
- Clinic of Endocrinology, Diabetes and Metabolism, University Hospital Basel, CH-4031 Basel, Switzerland.,Department of Biomedicine (DBM), University of Basel, University Hospital Basel, CH-4031 Basel, Switzerland.,Correspondence:
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34
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Ma Y, Lee G, Heo SY, Roh YS. Oxidative Stress Is a Key Modulator in the Development of Nonalcoholic Fatty Liver Disease. Antioxidants (Basel) 2021; 11:antiox11010091. [PMID: 35052595 PMCID: PMC8772974 DOI: 10.3390/antiox11010091] [Citation(s) in RCA: 103] [Impact Index Per Article: 25.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 12/27/2021] [Accepted: 12/28/2021] [Indexed: 12/14/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide, and scientific studies consistently report that NAFLD development can be accelerated by oxidative stress. Oxidative stress can induce the progression of NAFLD to NASH by stimulating Kupffer cells, hepatic stellate cells, and hepatocytes. Therefore, studies are underway to identify the role of antioxidants in the treatment of NAFLD. In this review, we have summarized the origins of reactive oxygen species (ROS) in cells, the relationship between ROS and NAFLD, and have discussed the use of antioxidants as therapeutic agents for NAFLD.
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Affiliation(s)
- Yuanqiang Ma
- College of Pharmacy and Medical Research Center, Chungbuk National University, Cheongju 28160, Korea; (Y.M.); (G.L.)
| | - Gyurim Lee
- College of Pharmacy and Medical Research Center, Chungbuk National University, Cheongju 28160, Korea; (Y.M.); (G.L.)
| | - Su-Young Heo
- College of Veterinary Medicine, Jeonbuk National University, Jeonju 54896, Korea
- Correspondence: (S.-Y.H.); (Y.-S.R.)
| | - Yoon-Seok Roh
- College of Pharmacy and Medical Research Center, Chungbuk National University, Cheongju 28160, Korea; (Y.M.); (G.L.)
- Correspondence: (S.-Y.H.); (Y.-S.R.)
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35
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Zhang J, Liu Q, He J, Li Y. Novel Therapeutic Targets in Liver Fibrosis. Front Mol Biosci 2021; 8:766855. [PMID: 34805276 PMCID: PMC8602792 DOI: 10.3389/fmolb.2021.766855] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Accepted: 10/18/2021] [Indexed: 02/05/2023] Open
Abstract
Liver fibrosis is end-stage liver disease that can be rescued. If irritation continues due to viral infection, schistosomiasis and alcoholism, liver fibrosis can progress to liver cirrhosis and even cancer. The US Food and Drug Administration has not approved any drugs that act directly against liver fibrosis. The only treatments currently available are drugs that eliminate pathogenic factors, which show poor efficacy; and liver transplantation, which is expensive. This highlights the importance of clarifying the mechanism of liver fibrosis and searching for new treatments against it. This review summarizes how parenchymal, nonparenchymal cells, inflammatory cells and various processes (liver fibrosis, hepatic stellate cell activation, cell death and proliferation, deposition of extracellular matrix, cell metabolism, inflammation and epigenetics) contribute to liver fibrosis. We highlight discoveries of novel therapeutic targets, which may provide new insights into potential treatments for liver fibrosis.
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Affiliation(s)
- Jinhang Zhang
- Laboratory of Clinical Pharmacy and Adverse Drug Reaction, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Sichuan, China
| | - Qinhui Liu
- Laboratory of Clinical Pharmacy and Adverse Drug Reaction, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Sichuan, China
| | - Jinhan He
- Laboratory of Clinical Pharmacy and Adverse Drug Reaction, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Sichuan, China.,Department of Pharmacy, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Sichuan, China
| | - Yanping Li
- Laboratory of Clinical Pharmacy and Adverse Drug Reaction, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Sichuan, China
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36
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Tong H, Li X, Zhang J, Gong L, Sun W, Calderon V, Zhang X, Li Y, Gadzinski A, Langdon WY, Reizis B, Zou Y, Gu H. Ubiquitin Ligases CBL and CBL-B Maintain the Homeostasis and Immune Quiescence of Dendritic Cells. Front Immunol 2021; 12:757231. [PMID: 34630435 PMCID: PMC8494778 DOI: 10.3389/fimmu.2021.757231] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Accepted: 09/06/2021] [Indexed: 12/15/2022] Open
Abstract
Dendritic cells (DCs) are composed of multiple lineages of hematopoietic cells and orchestrate immune responses upon detecting the danger and inflammatory signals associated with pathogen and damaged tissues. Under steady-state, DCs are maintained at limited numbers and the functionally quiescent status. While it is known that a fine balance in the DC homeostasis and activation status is also important to prevent autoimmune diseases and hyperinflammation, mechanisms that control DC development and activation under stead-state remain not fully understood. Here we show that DC-specific ablation of CBL and CBL-B (CBL-/-CBL-B-/-) leads to spontaneous liver inflammation and fibrosis and early death of the mice. The mutant mice have a marked expansion of classic CD8α+/CD103+ DCs (cDC1s) in peripheral lymphoid organs and the liver. These DCs exhibit atypical activation phenotypes characterized by an increased production of inflammatory cytokines and chemokines but not the cell surface MHC-II and costimulatory ligands. While the mutant mice also have massive T cell activation, lymphocytes are not required for the disease development. The CBL-/-CBL-B-/- mutation enhances FLT3-mTOR signaling, due to defective FLT3 ubiquitination and degradation. Blockade of FLT3-mTOR signaling normalizes the homeostasis of cDC1s and attenuates liver inflammation. Our result thus reveals a critical role of CBLs in the maintenance of DC homeostasis and immune quiescence. This regulation could be relevant to liver inflammatory diseases and fibrosis in humans.
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Affiliation(s)
- Haijun Tong
- Molecular Immunology Research Unit, Montreal Clinic Research Institute, Montreal, QC, Canada.,Department of Microbiology and Immunology, University of Montreal, Montreal, QC, Canada.,Department of Biochemistry and Molecular Medicine, University of Montreal, Montreal, QC, Canada
| | - Xin Li
- Molecular Immunology Research Unit, Montreal Clinic Research Institute, Montreal, QC, Canada.,Department of Microbiology and Immunology, University of Montreal, Montreal, QC, Canada.,Department of Biochemistry and Molecular Medicine, University of Montreal, Montreal, QC, Canada
| | - Jinping Zhang
- Institute of Biology and Medical Science, SooChow University, Jiangsu, China
| | - Liying Gong
- Molecular Immunology Research Unit, Montreal Clinic Research Institute, Montreal, QC, Canada.,Division of Experimental Medicine, McGill University, Montreal, QC, Canada
| | - Weili Sun
- Molecular Immunology Research Unit, Montreal Clinic Research Institute, Montreal, QC, Canada.,Division of Experimental Medicine, McGill University, Montreal, QC, Canada
| | - Virginie Calderon
- Molecular Immunology Research Unit, Montreal Clinic Research Institute, Montreal, QC, Canada
| | - Xiaochen Zhang
- Molecular Immunology Research Unit, Montreal Clinic Research Institute, Montreal, QC, Canada
| | - Yue Li
- Molecular Immunology Research Unit, Montreal Clinic Research Institute, Montreal, QC, Canada
| | - Adeline Gadzinski
- Molecular Immunology Research Unit, Montreal Clinic Research Institute, Montreal, QC, Canada
| | - Wallace Y Langdon
- School of Biomedical Sciences, University of Western Australia, Crawley, WA, Australia
| | - Boris Reizis
- Department of Pathology, New York University Langone Medical Center, New York, NY, United States.,Department of Medicine, New York University Langone Medical Center, New York, NY, United States
| | - Yongrui Zou
- The Feinstein Institute for Medical Research, Manhasset, New York, NY, United States
| | - Hua Gu
- Molecular Immunology Research Unit, Montreal Clinic Research Institute, Montreal, QC, Canada.,Department of Microbiology and Immunology, University of Montreal, Montreal, QC, Canada.,Department of Biochemistry and Molecular Medicine, University of Montreal, Montreal, QC, Canada.,Division of Experimental Medicine, McGill University, Montreal, QC, Canada
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37
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Cunningham RP, Porat-Shliom N. Liver Zonation - Revisiting Old Questions With New Technologies. Front Physiol 2021; 12:732929. [PMID: 34566696 PMCID: PMC8458816 DOI: 10.3389/fphys.2021.732929] [Citation(s) in RCA: 79] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Accepted: 08/10/2021] [Indexed: 12/12/2022] Open
Abstract
Despite the ever-increasing prevalence of non-alcoholic fatty liver disease (NAFLD), the etiology and pathogenesis remain poorly understood. This is due, in part, to the liver's complex physiology and architecture. The liver maintains glucose and lipid homeostasis by coordinating numerous metabolic processes with great efficiency. This is made possible by the spatial compartmentalization of metabolic pathways a phenomenon known as liver zonation. Despite the importance of zonation to normal liver function, it is unresolved if and how perturbations to liver zonation can drive hepatic pathophysiology and NAFLD development. While hepatocyte heterogeneity has been identified over a century ago, its examination had been severely hindered due to technological limitations. Recent advances in single cell analysis and imaging technologies now permit further characterization of cells across the liver lobule. This review summarizes the advances in examining liver zonation and elucidating its regulatory role in liver physiology and pathology. Understanding the spatial organization of metabolism is vital to further our knowledge of liver disease and to provide targeted therapeutic avenues.
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Affiliation(s)
- Rory P Cunningham
- Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, United States
| | - Natalie Porat-Shliom
- Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, United States
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38
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Abstract
In this review, Lee and Olefsky discuss the characteristics of chronic inflammation in the major metabolic tissues and how obesity triggers these events, including a focus on the role of adipose tissue hypoxia and macrophage-derived exosomes. Obesity is the most common cause of insulin resistance, and the current obesity epidemic is driving a parallel rise in the incidence of T2DM. It is now widely recognized that chronic, subacute tissue inflammation is a major etiologic component of the pathogenesis of insulin resistance and metabolic dysfunction in obesity. Here, we summarize recent advances in our understanding of immunometabolism. We discuss the characteristics of chronic inflammation in the major metabolic tissues and how obesity triggers these events, including a focus on the role of adipose tissue hypoxia and macrophage-derived exosomes. Last, we also review current and potential new therapeutic strategies based on immunomodulation.
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Affiliation(s)
- Yun Sok Lee
- Department of Medicine, Division of Endocrinology and Metabolism, University of California at San Diego, La Jolla, California 92093, USA
| | - Jerrold Olefsky
- Department of Medicine, Division of Endocrinology and Metabolism, University of California at San Diego, La Jolla, California 92093, USA
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39
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Zhu B, Chan SL, Li J, Li K, Wu H, Cui K, Chen H. Non-alcoholic Steatohepatitis Pathogenesis, Diagnosis, and Treatment. Front Cardiovasc Med 2021; 8:742382. [PMID: 34557535 PMCID: PMC8452937 DOI: 10.3389/fcvm.2021.742382] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Accepted: 08/13/2021] [Indexed: 12/12/2022] Open
Abstract
There has been a rise in the prevalence of non-alcohol fatty liver disease (NAFLD) due to the popularity of western diets and sedentary lifestyles. One quarter of NAFLD patients is diagnosed with non-alcoholic steatohepatitis (NASH), with histological evidence not only of fat accumulation in hepatocytes but also of liver cell injury and death due to long-term inflammation. Severe NASH patients have increased risks of cirrhosis and liver cancer. In this review, we discuss the pathogenesis and current methods of diagnosis for NASH, and current status of drug development for this life-threatening liver disease.
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Affiliation(s)
| | | | | | | | | | | | - Hong Chen
- Department of Surgery, Vascular Biology Program, Harvard Medical School, Boston Children's Hospital, Boston, MA, United States
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40
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Pervin M, Hasan I, Kobir MA, Akter L, Karim MR. Immunophenotypic analysis of the distribution of hepatic macrophages, lymphocytes and hepatic stellate cells in the adult rat liver. Anat Histol Embryol 2021; 50:736-745. [PMID: 34128248 DOI: 10.1111/ahe.12718] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2021] [Revised: 05/23/2021] [Accepted: 05/31/2021] [Indexed: 01/22/2023]
Abstract
The liver consists of parenchymal hepatocytes and non-parenchymal cells. Non-parenchymal cells, Kupffer cells, hepatic stellate cells and cholangiocytes have crucial roles in liver homeostasis and liver pathology. To establish baseline data, this study investigated immunohistochemically the distribution of non-parenchymal cells in perivenular areas (PV), periportal areas (PP) and Glisson's sheath (GS) of adult rat liver. Liver tissues were collected from the left lateral lobe of rats. CD163-positive macrophages were seen along the sinusoid of PV and PP areas, indicating Kupffer cells. Double immunofluorescence showed, Kupffer cells partly co-expressed CD68 and MHC class II antigens in the liver. The numbers of Kupffer cells were significantly high in PP areas as compared with PV or GS areas. CD68-positive exudative macrophages were highly localized in PP and GS areas and a comparatively low PV area. MHC class II-positive dendritic cells (activated macrophages) were localized mainly in GS. Granzyme B-positive NK cells were mainly localized in the Glisson's sheath. CD3-positive T cells and CD20-positive B cells were distributed along the sinusoids of the PP and PV areas of hepatic lobules. Vimentin and glial fibrillary acidic protein (GFAP)-positive hepatic stellate cells were localized along sinusoids in the hepatic lobules of the liver. Cholangiocytes reacting to cytokeratin 19 were seen on interlobular bile ducts in Glisson's sheath of the liver. This study shows that heterogeneous macrophage populations, liver-resident lymphocytes and hepatic stellate cells localized in PP and PV areas or GS areas of the liver with cells specific patterns.
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Affiliation(s)
- Munmun Pervin
- Department of Pathology, Faculty of Veterinary Science, Bangladesh Agricultural University, Mymensingh, Bangladesh
| | - Imam Hasan
- Department of Anatomy and Histology, Faculty of Veterinary Science, Bangladesh Agricultural University, Mymensingh, Bangladesh
| | - Md Alamgir Kobir
- Department of Anatomy and Histology, Faculty of Veterinary Science, Bangladesh Agricultural University, Mymensingh, Bangladesh
| | - Latifa Akter
- Department of Anatomy and Histology, Faculty of Veterinary Science, Bangladesh Agricultural University, Mymensingh, Bangladesh
| | - Mohammad Rabiul Karim
- Department of Anatomy and Histology, Faculty of Veterinary Science, Bangladesh Agricultural University, Mymensingh, Bangladesh
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41
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English K, Bowen DG, Bertolino P. Zone defence - the gut microbiota position macrophages for optimal liver protection. Immunol Cell Biol 2021; 99:565-569. [PMID: 34080232 DOI: 10.1111/imcb.12476] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Accepted: 04/28/2021] [Indexed: 01/06/2023]
Affiliation(s)
- Kieran English
- Centenary Institute and AW Morrow Gastroenterology and Liver Centre, University of Sydney and Royal Prince Alfred Hospital, Sydney, NSW, Australia
| | - David G Bowen
- Centenary Institute and AW Morrow Gastroenterology and Liver Centre, University of Sydney and Royal Prince Alfred Hospital, Sydney, NSW, Australia
| | - Patrick Bertolino
- Centenary Institute and AW Morrow Gastroenterology and Liver Centre, University of Sydney and Royal Prince Alfred Hospital, Sydney, NSW, Australia
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42
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An SB, Yang K, Kim CW, Choi SH, Kim E, Kim SD, Koh JS. Longitudinal Imaging of Liver Cancer Using MicroCT and Nanoparticle Contrast Agents in CRISPR/Cas9-Induced Liver Cancer Mouse Model. Technol Cancer Res Treat 2021; 20:15330338211016466. [PMID: 34039112 PMCID: PMC8165521 DOI: 10.1177/15330338211016466] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
Introduction: Micro-computed tomography with nanoparticle contrast agents may be a suitable tool for monitoring the time course of the development and progression of tumors. Here, we suggest a practical and convenient experimental method for generating and longitudinally imaging murine liver cancer models. Methods: Liver cancer was induced in 6 experimental mice by injecting clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeats-associated protein 9 plasmids causing mutations in genes expressed by hepatocytes. Nanoparticle agents are captured by Kupffer cells and detected by micro-computed tomography, thereby enabling longitudinal imaging. A total of 9 mice were used for the experiment. Six mice were injected with both plasmids and contrast, 2 injected with contrast alone, and one not injected with either agent. Micro-computed tomography images were acquired every 2- up to 14-weeks after cancer induction. Results: Liver cancer was first detected by micro-computed tomography at 8 weeks. The mean value of hepatic parenchymal attenuation remained almost unchanged over time, although the standard deviation of attenuation, reflecting heterogeneous contrast enhancement of the hepatic parenchyma, increased slowly over time in all mice. Histopathologically, heterogeneous distribution and aggregation of Kupffer cells was more prominent in the experimental group than in the control group. Heterogeneous enhancement of hepatic parenchyma, which could cause image quality deterioration and image misinterpretation, was observed and could be due to variation in Kupffer cells distribution. Conclusion: Micro-computed tomography with nanoparticle contrast is useful in evaluating the induction and characteristics of liver cancer, determining appropriate size of liver cancer for testing, and confirming therapeutic response.
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Affiliation(s)
- Sang Bu An
- Department of Radiology, 37995Korea Institute of Radiological and Medical Sciences, Nowon-gu, Seoul, Korea
| | - Kwangmo Yang
- Department of Radiation Oncology, 37995Korea Institute of Radiological and Medical Sciences, Nowon-gu, Seoul, Korea
| | - Chang Won Kim
- Department of Radiology, School of Medicine and Biomedical Research Institute, 220312Pusan National University, Pusan National University Hospital, Busan, Korea
| | - Si Ho Choi
- Research Center, 222204Dongnam Institute of Radiological and Medical Sciences, Busan, Korea
| | - Eunji Kim
- Department of Radiation Oncology, 37995Korea Institute of Radiological and Medical Sciences, Nowon-gu, Seoul, Korea
| | - Sung Dae Kim
- Research Center, 222204Dongnam Institute of Radiological and Medical Sciences, Busan, Korea
| | - Jae Soo Koh
- Department of Pathology, 37995Korea Institute of Radiological and Medical Sciences, Nowon-gu, Seoul, Korea
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43
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Miura I, Komine S, Okada K, Wada S, Warabi E, Uchida F, Oh S, Suzuki H, Mizokami Y, Shoda J. Prevention of non-alcoholic steatohepatitis by long-term exercise via the induction of phenotypic changes in Kupffer cells of hyperphagic obese mice. Physiol Rep 2021; 9:e14859. [PMID: 33991461 PMCID: PMC8123550 DOI: 10.14814/phy2.14859] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Revised: 04/07/2021] [Accepted: 04/12/2021] [Indexed: 01/01/2023] Open
Abstract
Exercise ameliorates nonalcoholic fatty liver disease (NAFLD) by inducing phenotypic changes in Kupffer cells (KCs). p62/Sqstm1-knockout (p62-KO) mice develop NAFLD alongside hyperphagia-induced obesity. We evaluated (1) the effects of long-term exercise on the foreign-body phagocytic capacity of KCs, their surface marker expression, and the production of steroid hormones in p62-KO mice; and (2) whether long-term exercise prevented the development of non-alcoholic steatohepatitis (NASH) in p62-KO mice fed a high-fat diet (HFD). In experiment 1, 30-week-old male p62-KO mice were allocated to resting (p62-KO-Rest) or exercise (p62-KO-Ex) groups, and the latter performed long-term exercise over 4 weeks. Then, the phenotype of their KCs was compared to that of p62-KO-Rest and wild-type (WT) mice. In experiment 2, 5-week-old male p62-KO mice that were fed a HFD performed long-term exercise over 12 weeks. In experiment 1, the phagocytic capacity of KCs and the proportion of CD68-positive cells were lower in the p62-KO-Rest group than in the WT group, but they increased with long-term exercise. The percentage of CD11b-positive KCs was higher in the p62-KO-Rest group than in the WT group, but lower in the p62-KO-Ex group. The circulating dehydroepiandrosterone (DHEA) concentration was higher in p62-KO-Ex mice than in p62-KO-Rest mice. In experiment 2, the body mass and composition of the p62-KO-Rest and p62-KO-Ex groups were similar, but the hepatomegaly, hepatic inflammation, and fibrosis were less marked in p62-KO-Ex mice. The DHEA concentration was higher in p62-KO-Ex mice than in WT or p62-KO-Rest mice. Thus, long-term exercise restores the impaired phagocytic capacity of KCs in NAFLD obese mice, potentially through greater DHEA production, and prevents the development of NASH by ameliorating hepatic inflammation and fibrogenesis. These results suggest a molecular mechanism for the beneficial effect of exercise in the management of patients with NAFLD.
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Affiliation(s)
- Ikuru Miura
- Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba-shi, Ibaraki, Japan
| | - Shoichi Komine
- Faculty of Human Care, Department of Acupuncture and Moxibustion, Teikyo Heisei University, Toshima-ku, Tokyo, Japan.,Faculty of Medicine, University of Tsukuba, Tsukuba-shi, Ibaraki, Japan
| | - Kosuke Okada
- Tsukuba Preventive Medicine Research Center, University of Tsukuba Hospital, Tsukuba-shi, Ibaraki, Japan
| | - Shota Wada
- Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba-shi, Ibaraki, Japan
| | - Eiji Warabi
- Division of Biomedical Sciences, Faculty of Medicine, University of Tsukuba, Tsukuba-shi, Ibaraki, Japan
| | - Fumihiko Uchida
- Faculty of Medicine, University of Tsukuba, Tsukuba-shi, Ibaraki, Japan
| | - Sechang Oh
- Faculty of Medicine, University of Tsukuba, Tsukuba-shi, Ibaraki, Japan
| | - Hideo Suzuki
- Faculty of Medicine, University of Tsukuba, Tsukuba-shi, Ibaraki, Japan.,Tsukuba Preventive Medicine Research Center, University of Tsukuba Hospital, Tsukuba-shi, Ibaraki, Japan
| | - Yuji Mizokami
- Faculty of Medicine, University of Tsukuba, Tsukuba-shi, Ibaraki, Japan
| | - Junichi Shoda
- Faculty of Medicine, University of Tsukuba, Tsukuba-shi, Ibaraki, Japan
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44
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On Iron Metabolism and Its Regulation. Int J Mol Sci 2021; 22:ijms22094591. [PMID: 33925597 PMCID: PMC8123811 DOI: 10.3390/ijms22094591] [Citation(s) in RCA: 209] [Impact Index Per Article: 52.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 04/14/2021] [Accepted: 04/20/2021] [Indexed: 02/07/2023] Open
Abstract
Iron is a critical metal for several vital biological processes. Most of the body’s iron is bound to hemoglobin in erythrocytes. Iron from senescent red blood cells is recycled by macrophages in the spleen, liver and bone marrow. Dietary iron is taken up by the divalent metal transporter 1 (DMT1) in enterocytes and transported to portal blood via ferroportin (FPN), where it is bound to transferrin and taken up by hepatocytes, macrophages and bone marrow cells via transferrin receptor 1 (TfR1). While most of the physiologically active iron is bound hemoglobin, the major storage of most iron occurs in the liver in a ferritin-bound fashion. In response to an increased iron load, hepatocytes secrete the peptide hormone hepcidin, which binds to and induces internalization and degradation of the iron transporter FPN, thus controlling the amount of iron released from the cells into the blood. This review summarizes the key mechanisms and players involved in cellular and systemic iron regulation.
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45
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Shi Y, Su W, Zhang L, Shi C, Zhou J, Wang P, Wang H, Shi X, Wei S, Wang Q, Auwerx J, Schoonjans K, Yu Y, Pan R, Zhou H, Lu L. TGR5 Regulates Macrophage Inflammation in Nonalcoholic Steatohepatitis by Modulating NLRP3 Inflammasome Activation. Front Immunol 2021; 11:609060. [PMID: 33692776 PMCID: PMC7937818 DOI: 10.3389/fimmu.2020.609060] [Citation(s) in RCA: 61] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Accepted: 12/30/2020] [Indexed: 12/30/2022] Open
Abstract
Nonalcoholic steatohepatitis (NASH) is a chronic liver disease associated with dysregulation of liver metabolism and inflammation. G-protein coupled bile acid receptor 1 (TGR5) is a cell surface receptor that is involved in multiple metabolic pathways. However, the functions of TGR5 in regulating macrophage innate immune activation in NASH remain unclear. Here, we found that TGR5 expression was decreased in liver tissues from humans and mice with NASH. Compared to wild type (WT) mice, TGR5-knockout (TGR5−/−) mice exhibited exacerbated liver damage, increased levels of proinflammatory factors, and enhanced M1 macrophage polarization. Moreover, TGR5 deficiency facilitated M1 macrophage polarization by promoting NLRP3 inflammasome activation and caspase-1 cleavage. Taken together, our findings revealed that TGR5 signaling attenuated liver steatosis and inflammation and inhibited NLRP3-mediated M1 macrophage polarization in NASH.
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Affiliation(s)
- Yong Shi
- Jiangsu Key Laboratory of Molecular and Translational Cancer Research, The Affiliated Cancer Hospital (Jiangsu Cancer Hospital), Nanjing Medical University, Nanjing, China.,Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University & Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China.,State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China.,Jiangsu Collaborative Innovation Center of Biomedical Functional Materials, College of Chemistry and Materials Science, Nanjing Normal University, Nanjing, China.,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing, China
| | - Wantong Su
- Jiangsu Key Laboratory of Molecular and Translational Cancer Research, The Affiliated Cancer Hospital (Jiangsu Cancer Hospital), Nanjing Medical University, Nanjing, China.,Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University & Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China.,State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China.,Jiangsu Collaborative Innovation Center of Biomedical Functional Materials, College of Chemistry and Materials Science, Nanjing Normal University, Nanjing, China.,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing, China
| | - Lei Zhang
- Jiangsu Key Laboratory of Molecular and Translational Cancer Research, The Affiliated Cancer Hospital (Jiangsu Cancer Hospital), Nanjing Medical University, Nanjing, China.,Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University & Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China.,State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China.,Jiangsu Collaborative Innovation Center of Biomedical Functional Materials, College of Chemistry and Materials Science, Nanjing Normal University, Nanjing, China.,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing, China
| | - Chengyu Shi
- Jiangsu Key Laboratory of Molecular and Translational Cancer Research, The Affiliated Cancer Hospital (Jiangsu Cancer Hospital), Nanjing Medical University, Nanjing, China.,Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University & Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China.,State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China.,Jiangsu Collaborative Innovation Center of Biomedical Functional Materials, College of Chemistry and Materials Science, Nanjing Normal University, Nanjing, China.,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing, China
| | - Jinren Zhou
- Jiangsu Key Laboratory of Molecular and Translational Cancer Research, The Affiliated Cancer Hospital (Jiangsu Cancer Hospital), Nanjing Medical University, Nanjing, China.,Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University & Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China.,State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China.,Jiangsu Collaborative Innovation Center of Biomedical Functional Materials, College of Chemistry and Materials Science, Nanjing Normal University, Nanjing, China.,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing, China
| | - Peng Wang
- Jiangsu Key Laboratory of Molecular and Translational Cancer Research, The Affiliated Cancer Hospital (Jiangsu Cancer Hospital), Nanjing Medical University, Nanjing, China.,Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University & Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China.,State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China.,Jiangsu Collaborative Innovation Center of Biomedical Functional Materials, College of Chemistry and Materials Science, Nanjing Normal University, Nanjing, China.,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing, China
| | - Hao Wang
- Jiangsu Key Laboratory of Molecular and Translational Cancer Research, The Affiliated Cancer Hospital (Jiangsu Cancer Hospital), Nanjing Medical University, Nanjing, China.,Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University & Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China.,State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China.,Jiangsu Collaborative Innovation Center of Biomedical Functional Materials, College of Chemistry and Materials Science, Nanjing Normal University, Nanjing, China.,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing, China
| | - Xiaoli Shi
- Jiangsu Key Laboratory of Molecular and Translational Cancer Research, The Affiliated Cancer Hospital (Jiangsu Cancer Hospital), Nanjing Medical University, Nanjing, China.,Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University & Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China.,State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China.,Jiangsu Collaborative Innovation Center of Biomedical Functional Materials, College of Chemistry and Materials Science, Nanjing Normal University, Nanjing, China.,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing, China
| | - Song Wei
- Jiangsu Key Laboratory of Molecular and Translational Cancer Research, The Affiliated Cancer Hospital (Jiangsu Cancer Hospital), Nanjing Medical University, Nanjing, China.,Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University & Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China.,State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China.,Jiangsu Collaborative Innovation Center of Biomedical Functional Materials, College of Chemistry and Materials Science, Nanjing Normal University, Nanjing, China.,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing, China
| | - Qi Wang
- Jiangsu Key Laboratory of Molecular and Translational Cancer Research, The Affiliated Cancer Hospital (Jiangsu Cancer Hospital), Nanjing Medical University, Nanjing, China.,Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University & Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China.,State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China.,Jiangsu Collaborative Innovation Center of Biomedical Functional Materials, College of Chemistry and Materials Science, Nanjing Normal University, Nanjing, China.,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing, China
| | - Johan Auwerx
- Metabolic Signaling, School of Life Sciences, Institute of Bioengineering, Ecole Polytechnique Federale de Lausanne, Lausanne, Switzerland
| | - Kristina Schoonjans
- Metabolic Signaling, School of Life Sciences, Institute of Bioengineering, Ecole Polytechnique Federale de Lausanne, Lausanne, Switzerland
| | - Yue Yu
- Jiangsu Key Laboratory of Molecular and Translational Cancer Research, The Affiliated Cancer Hospital (Jiangsu Cancer Hospital), Nanjing Medical University, Nanjing, China.,Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University & Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China.,State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China.,Jiangsu Collaborative Innovation Center of Biomedical Functional Materials, College of Chemistry and Materials Science, Nanjing Normal University, Nanjing, China.,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing, China
| | - Rui Pan
- Jiangsu Key Laboratory of Molecular and Translational Cancer Research, The Affiliated Cancer Hospital (Jiangsu Cancer Hospital), Nanjing Medical University, Nanjing, China
| | - Haoming Zhou
- Jiangsu Key Laboratory of Molecular and Translational Cancer Research, The Affiliated Cancer Hospital (Jiangsu Cancer Hospital), Nanjing Medical University, Nanjing, China.,Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University & Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China.,State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China.,Jiangsu Collaborative Innovation Center of Biomedical Functional Materials, College of Chemistry and Materials Science, Nanjing Normal University, Nanjing, China.,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing, China
| | - Ling Lu
- Jiangsu Key Laboratory of Molecular and Translational Cancer Research, The Affiliated Cancer Hospital (Jiangsu Cancer Hospital), Nanjing Medical University, Nanjing, China.,Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University & Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China.,State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China.,Jiangsu Collaborative Innovation Center of Biomedical Functional Materials, College of Chemistry and Materials Science, Nanjing Normal University, Nanjing, China.,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing, China
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Peroxisome proliferator-activated receptors in the pathogenesis and therapies of liver fibrosis. Pharmacol Ther 2020; 222:107791. [PMID: 33321113 DOI: 10.1016/j.pharmthera.2020.107791] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Accepted: 12/04/2020] [Indexed: 12/12/2022]
Abstract
Liver fibrosis is a dynamic wound-healing process associated with the deposition of extracellular matrix produced by myofibroblasts. HSCs activation, inflammation, oxidative stress, steatosis and aging play critical roles in the progression of liver fibrosis, which is correlated with the regulation of the peroxisome proliferator-activated receptor (PPAR) pathway. As nuclear receptors, PPARs reduce inflammatory response, regulate lipid metabolism, and inhibit fibrogenesis in the liver associated with aging. Thus, PPAR ligands have been investigated as possible therapeutic agents. Mounting evidence indicated that some PPAR agonists could reverse steatohepatitis and liver fibrosis. Consequently, targeting PPARs might be a promising and novel therapeutic option against liver fibrosis. This review summarizes recent studies on the role of PPARs on the pathogenesis and treatment of liver fibrosis.
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Ouyang B, Poon W, Zhang YN, Lin ZP, Kingston BR, Tavares AJ, Zhang Y, Chen J, Valic MS, Syed AM, MacMillan P, Couture-Senécal J, Zheng G, Chan WCW. The dose threshold for nanoparticle tumour delivery. NATURE MATERIALS 2020; 19:1362-1371. [PMID: 32778816 DOI: 10.1038/s41563-020-0755-z] [Citation(s) in RCA: 335] [Impact Index Per Article: 67.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/12/2019] [Accepted: 06/30/2020] [Indexed: 05/24/2023]
Abstract
Nanoparticle delivery to solid tumours over the past ten years has stagnated at a median of 0.7% of the injected dose. Varying nanoparticle designs and strategies have yielded only minor improvements. Here we discovered a dose threshold for improving nanoparticle tumour delivery: 1 trillion nanoparticles in mice. Doses above this threshold overwhelmed Kupffer cell uptake rates, nonlinearly decreased liver clearance, prolonged circulation and increased nanoparticle tumour delivery. This enabled up to 12% tumour delivery efficiency and delivery to 93% of cells in tumours, and also improved the therapeutic efficacy of Caelyx/Doxil. This threshold was robust across different nanoparticle types, tumour models and studies across ten years of the literature. Our results have implications for human translation and highlight a simple, but powerful, principle for designing nanoparticle cancer treatments.
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Affiliation(s)
- Ben Ouyang
- MD/PhD Program, University of Toronto, Toronto, Ontario, Canada
- Institute of Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada
- Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, Canada
| | - Wilson Poon
- Institute of Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada
- Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, Canada
| | - Yi-Nan Zhang
- Institute of Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada
- Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, Canada
| | - Zachary P Lin
- Institute of Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada
- Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, Canada
| | - Benjamin R Kingston
- Institute of Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada
- Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, Canada
| | - Anthony J Tavares
- Institute of Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada
- Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, Canada
- School of Life Sciences, Faculty of Humanities and Social Sciences, Sheridan College, Brampton, Ontario, Canada
| | - Yuwei Zhang
- Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, Canada
- Department of Chemistry, University of Toronto, Toronto, Ontario, Canada
| | - Juan Chen
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Michael S Valic
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Abdullah M Syed
- Institute of Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada
- Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, Canada
- J. David Gladstone Institutes, San Francisco, CA, USA
| | - Presley MacMillan
- Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, Canada
- Department of Chemistry, University of Toronto, Toronto, Ontario, Canada
| | - Julien Couture-Senécal
- Institute of Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada
- Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, Canada
- Division of Engineering Science, University of Toronto, Toronto, Ontario, Canada
| | - Gang Zheng
- Institute of Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
| | - Warren C W Chan
- Institute of Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada.
- Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, Canada.
- Department of Chemistry, University of Toronto, Toronto, Ontario, Canada.
- Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, Ontario, Canada.
- Department of Material Science and Engineering, University of Toronto, Toronto, Ontario, Canada.
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Bhandari S, Li R, Simón-Santamaría J, McCourt P, Johansen SD, Smedsrød B, Martinez-Zubiaurre I, Sørensen KK. Transcriptome and proteome profiling reveal complementary scavenger and immune features of rat liver sinusoidal endothelial cells and liver macrophages. BMC Mol Cell Biol 2020; 21:85. [PMID: 33246411 PMCID: PMC7694354 DOI: 10.1186/s12860-020-00331-9] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2020] [Accepted: 11/18/2020] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Liver sinusoidal endothelial cells (LSECs) and Kupffer cells (KCs; liver resident macrophages) form the body's most effective scavenger cell system for the removal of harmful blood-borne substances, ranging from modified self-proteins to pathogens and xenobiotics. Controversies in the literature regarding the LSEC phenotype pose a challenge when determining distinct functionalities of KCs and LSECs. This may be due to overlapping functions of the two cells, insufficient purification and/or identification of the cells, rapid dedifferentiation of LSECs in vitro, or species differences. We therefore characterized and quantitatively compared expressed gene products of freshly isolated, highly pure LSECs (fenestrated SE-1/FcγRIIb2+) and KCs (CD11b/c+) from Sprague Dawley, Crl:CD (SD), male rats using high throughput mRNA-sequencing and label-free proteomics. RESULTS We observed a robust correlation between the proteomes and transcriptomes of the two cell types. Integrative analysis of the global molecular profile demonstrated the immunological aspects of LSECs. The constitutive expression of several immune genes and corresponding proteins of LSECs bore some resemblance with the expression in macrophages. LSECs and KCs both expressed high levels of scavenger receptors (SR) and C-type lectins. Equivalent expression of SR-A1 (Msr1), mannose receptor (Mrc1), SR-B1 (Scarb1), and SR-B3 (Scarb2) suggested functional similarity between the two cell types, while functional distinction between the cells was evidenced by LSEC-specific expression of the SRs stabilin-1 (Stab1) and stabilin-2 (Stab2), and the C-type lectins LSECtin (Clec4g) and DC-SIGNR (Clec4m). Many immune regulatory factors were differentially expressed in LSECs and KCs, with one cell predominantly expressing a specific cytokine/chemokine and the other cell the cognate receptor, illustrating the complex cytokine milieu of the sinusoids. Both cells expressed genes and proteins involved in antigen processing and presentation, and lymphocyte co-stimulation. CONCLUSIONS Our findings support complementary and partly overlapping scavenging and immune functions of LSECs and KCs. This highlights the importance of including LSECs in studies of liver immunity, and liver clearance and toxicity of large molecule drugs and nano-formulations.
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Affiliation(s)
- Sabin Bhandari
- Department of Medical Biology, Vascular Biology Research Group, University of Tromsø (UiT) -The Arctic University of Norway, Hansine Hansens veg 18, N-9037, Tromsø, Norway
| | - Ruomei Li
- Department of Medical Biology, Vascular Biology Research Group, University of Tromsø (UiT) -The Arctic University of Norway, Hansine Hansens veg 18, N-9037, Tromsø, Norway
| | - Jaione Simón-Santamaría
- Department of Medical Biology, Vascular Biology Research Group, University of Tromsø (UiT) -The Arctic University of Norway, Hansine Hansens veg 18, N-9037, Tromsø, Norway
| | - Peter McCourt
- Department of Medical Biology, Vascular Biology Research Group, University of Tromsø (UiT) -The Arctic University of Norway, Hansine Hansens veg 18, N-9037, Tromsø, Norway
| | - Steinar Daae Johansen
- Department of Medical Biology, Vascular Biology Research Group, University of Tromsø (UiT) -The Arctic University of Norway, Hansine Hansens veg 18, N-9037, Tromsø, Norway.,Faculty of Biosciences and Aquaculture, Nord University, Bodø, Norway
| | - Bård Smedsrød
- Department of Medical Biology, Vascular Biology Research Group, University of Tromsø (UiT) -The Arctic University of Norway, Hansine Hansens veg 18, N-9037, Tromsø, Norway.
| | | | - Karen Kristine Sørensen
- Department of Medical Biology, Vascular Biology Research Group, University of Tromsø (UiT) -The Arctic University of Norway, Hansine Hansens veg 18, N-9037, Tromsø, Norway
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49
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Commensal-driven immune zonation of the liver promotes host defence. Nature 2020; 589:131-136. [PMID: 33239787 DOI: 10.1038/s41586-020-2977-2] [Citation(s) in RCA: 150] [Impact Index Per Article: 30.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Accepted: 09/11/2020] [Indexed: 12/21/2022]
Abstract
The liver connects the intestinal portal vasculature with the general circulation, using a diverse array of immune cells to protect from pathogens that translocate from the gut1. In liver lobules, blood flows from portal triads that are situated in periportal lobular regions to the central vein via a polarized sinusoidal network. Despite this asymmetry, resident immune cells in the liver are considered to be broadly dispersed across the lobule. This differs from lymphoid organs, in which immune cells adopt spatially biased positions to promote effective host defence2,3. Here we used quantitative multiplex imaging, genetic perturbations, transcriptomics, infection-based assays and mathematical modelling to reassess the relationship between the localization of immune cells in the liver and host protection. We found that myeloid and lymphoid resident immune cells concentrate around periportal regions. This asymmetric localization was not developmentally controlled, but resulted from sustained MYD88-dependent signalling induced by commensal bacteria in liver sinusoidal endothelial cells, which in turn regulated the composition of the pericellular matrix involved in the formation of chemokine gradients. In vivo experiments and modelling showed that this immune spatial polarization was more efficient than a uniform distribution in protecting against systemic bacterial dissemination. Together, these data reveal that liver sinusoidal endothelial cells sense the microbiome, actively orchestrating the localization of immune cells, to optimize host defence.
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Luo QJ, Sun MX, Guo YW, Tan SW, Wu XY, Abassa KK, Lin L, Liu HL, Jiang J, Wei XQ. Sodium butyrate protects against lipopolysaccharide-induced liver injury partially via the GPR43/ β-arrestin-2/NF-κB network. Gastroenterol Rep (Oxf) 2020; 9:154-165. [PMID: 34026223 PMCID: PMC8128024 DOI: 10.1093/gastro/goaa085] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 10/11/2020] [Accepted: 10/15/2020] [Indexed: 02/06/2023] Open
Abstract
Background Butyrate acts as a regulator in multiple inflammatory organ injuries. However, the role of butyrate in acute liver injury has not yet been fully explored. In the present study, we aimed to investigate the association between butyrate and lipopolysaccharide (LPS)-induced acute liver injury and the signaling pathways involved. Methods LPS-induced acute liver injury was induced by intraperitoneal injection of LPS (5 mg/kg) in G-protein-coupled receptor 43 (GPR43)-knockout (KO) and wild-type female C57BL/6 mice. Sodium butyrate (500mg/kg) was administered intraperitoneally 30 min prior to LPS exposure. Liver injury was detected by serum markers, tissue morphology, and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL). Pro-inflammatory-factor levels were detected by enzyme-linked immunosorbent assay and real-time polymerase chain reaction (RT-PCR). Cell models were first treated with sodium butyrate (4 μmol/mL), followed by LPS (1 μg/mL) half an hour later in GPR43 small interfering RNA (siRNA)-transfected or control RAW264.7 cells. Cell-inflammation status was evaluated through detecting pro-inflammatory-factor expression by RT-PCR and also through checking toll-like receptor 4/nuclear factor-κB (TLR4/NF-κB)-element levels including TLR4, TRAF6, IKKβ, IкBα, phospho-IкBα, p65, and phospho-p65 by Western blot. The interaction between GPR43 and β-arrestin-2 was tested by co-immunoprecipitation. Results Sodium butyrate reversed the LPS-induced tissue-morphology changes and high levels of serum alanine aminotransferase, aspartate transaminase, myeloperoxidase, TUNEL, and pro-inflammatory cytokines such as tumor necrosis factor-α and interleukin-6. The ameliorating effect of sodium butyrate was weakened in GPR43-KO mice and GPR43 siRNA RAW264.7 cells, compared with those of GPR43-positive controls. Sodium butyrate downregulated some elements of the TLR4/NF-κB pathway, including phospho-IκBα and phospho-p65, in RAW264.7 cells. Increased interactions between GPR43 and β-arrestin-2, and between β-arrestin-2 and IкBα were observed. Conclusion Sodium butyrate significantly attenuated LPS-induced liver injury by reducing the inflammatory response partially via the GPR43/β-arrestin-2/NF-κB signaling pathway.
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Affiliation(s)
- Qian-Jiang Luo
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China.,Department of Gastroenterology, The Eighth Affiliated Hospital of Sun Yat-sen University (Shenzhen Futian Hospital), Shenzhen, Guangdong, P. R. China
| | - Mei-Xing Sun
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Yun-Wei Guo
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Si-Wei Tan
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Xiao-Ying Wu
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Kodjo-Kunale Abassa
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Li Lin
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Hui-Ling Liu
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Jie Jiang
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Xiu-Qing Wei
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
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