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1
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Huang JC, Tong XL, Xiang MSW, Boumelhem BB, Foulis DP, Zhang M, McKenzie CA, McCaughan GW, Reinheckel T, Zhang HE, Gorrell MD. Dipeptidyl peptidase 9 (DPP9) depletion from hepatocytes in experimental primary liver cancer. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167819. [PMID: 40187163 DOI: 10.1016/j.bbadis.2025.167819] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2024] [Revised: 03/13/2025] [Accepted: 03/25/2025] [Indexed: 04/07/2025]
Abstract
Dipeptidyl peptidase 9 (DPP9) is an indispensable intracellular protease. Among its many molecular functions is suppression of the NLRP1 inflammasome. Inhibitors targeting all four proteases of the DPP4 family, including DPP9, can reduce tumour burden, including in mouse liver. To explore hepatocyte DPP9 in experimental hepatocellular carcinoma (HCC), we generated hepatocyte-specific DPP9-KO mice by crossing albumin-Cre mice with DPP9 floxed mice and treated sequentially with diethylnitrosamine, then with thioacetamide combined with an atherogenic high-fat diet until 28 weeks of age. DPP9-KO mice had less body, liver and subcutaneous adipose tissue mass, lower fasting plasma glucose and fewer small macroscopic liver nodules compared to DPP9-WT control mice. However, there were no differences in the total number of macroscopic liver nodules, or of microscopic tumour burden, inflammation, fibrosis or steatosis. Consistent with the known function of DPP9 to suppress NLRP1 activation, activated caspase-1 protein and inflammation markers Nfkbib, Cxcl10 and Ccl5 were elevated in DPP9-KO liver. The tumour suppressor protein p53 was increased and the autophagy proteins beclin1, LC3B and p62 were altered. In conclusion, hepatocyte-specific DPP9 gene deletion in experimental primary liver cancer improved energy metabolism and may reduce liver cancer initiation, via mechanisms that may include increased autophagy and tumour suppression.
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MESH Headings
- Animals
- Hepatocytes/pathology
- Hepatocytes/metabolism
- Hepatocytes/enzymology
- Mice
- Mice, Knockout
- Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/genetics
- Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/metabolism
- Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/deficiency
- Liver Neoplasms, Experimental/pathology
- Liver Neoplasms, Experimental/genetics
- Liver Neoplasms, Experimental/metabolism
- Liver Neoplasms, Experimental/chemically induced
- Carcinoma, Hepatocellular/pathology
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/metabolism
- Male
- Liver Neoplasms/pathology
- Liver Neoplasms/genetics
- Liver Neoplasms/metabolism
- Diet, High-Fat/adverse effects
- Mice, Inbred C57BL
- Inflammasomes/metabolism
- Liver/pathology
- Liver/metabolism
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Affiliation(s)
- JiaLi Carrie Huang
- Centenary Institute, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia
| | - Xinlin Linda Tong
- Centenary Institute, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia
| | - Michelle Sui Wen Xiang
- Centenary Institute, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia
| | - Badwi B Boumelhem
- Centenary Institute, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia
| | - Diarmid P Foulis
- Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, Australia
| | - MingChang Zhang
- Centenary Institute, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia
| | - Catriona A McKenzie
- Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, Australia
| | - Geoffrey W McCaughan
- Centenary Institute, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia; AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Sydney, Australia
| | - Thomas Reinheckel
- Institute of Molecular Medicine and Cell Research, Faculty of Medicine, University of Freiburg, Freiburg, Germany; German Cancer Consortium (DKTK), partner site Freiburg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany; Centre for Biological Signalling Studies BIOSS, University of Freiburg, Freiburg, Germany
| | - Hui E Zhang
- Centenary Institute, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia
| | - Mark D Gorrell
- Centenary Institute, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia.
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2
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Ronca V, Gerussi A, Collins P, Parente A, Oo YH, Invernizzi P. The liver as a central "hub" of the immune system: pathophysiological implications. Physiol Rev 2025; 105:493-539. [PMID: 39297676 DOI: 10.1152/physrev.00004.2023] [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: 05/18/2023] [Revised: 09/05/2024] [Accepted: 09/08/2024] [Indexed: 01/16/2025] Open
Abstract
The purpose of this review is to describe the immune function of the liver, guiding the reader from the homeostatic tolerogenic status to the aberrant activation demonstrated in chronic liver disease. An extensive description of the pathways behind the inflammatory modulation of the healthy liver will be provided focusing on the complex immune cell network residing within the liver. The limit of tolerance will be presented in the context of organ transplantation, seizing the limits of homeostatic mechanisms that fail in accepting the graft, progressing eventually toward rejection. The triggers and mechanisms behind chronic activation in metabolic liver conditions and viral hepatitis will be discussed. The last part of the review will be dedicated to one of the greatest paradoxes for a tolerogenic organ, developing autoimmunity. Through the description of the three most common autoimmune liver diseases, the autoimmune reaction against hepatocytes and biliary epithelial cells will be dissected.
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Affiliation(s)
- Vincenzo Ronca
- Centre for Liver and Gastro Research and National Institute for Health and Care Research (NIHR) Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
- Liver Unit, Queen Elizabeth Hospital University Hospital Birmingham National Health Service (NHS) Foundation Trust, Birmingham, United Kingdom
- Centre for Rare Diseases, European Reference Network Centre-Rare Liver, Birmingham, United Kingdom
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
- Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Humanitas Research Hospital, Milan, Italy
| | - Alessio Gerussi
- Division of Gastroenterology, Center for Autoimmune Liver Diseases, European Reference Network on Hepatological Diseases (ERN RARE-LIVER), IRCCS Fondazione San Gerardo dei Tintori, Monza, Italy
- Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Paul Collins
- VIB-UGent Center for Inflammation Research, Ghent, Belgium
- Department of Biomedical Molecular Biology, Faculty of Sciences, Ghent University, Ghent, Belgium
| | - Alessandro Parente
- Liver Unit, Queen Elizabeth Hospital University Hospital Birmingham National Health Service (NHS) Foundation Trust, Birmingham, United Kingdom
- Institute of Liver Studies, King's College Hospital NHS Foundation Trust, London, United Kingdom
| | - Ye Htun Oo
- Centre for Liver and Gastro Research and National Institute for Health and Care Research (NIHR) Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
- Liver Unit, Queen Elizabeth Hospital University Hospital Birmingham National Health Service (NHS) Foundation Trust, Birmingham, United Kingdom
- Centre for Rare Diseases, European Reference Network Centre-Rare Liver, Birmingham, United Kingdom
| | - Pietro Invernizzi
- Division of Gastroenterology, Center for Autoimmune Liver Diseases, European Reference Network on Hepatological Diseases (ERN RARE-LIVER), IRCCS Fondazione San Gerardo dei Tintori, Monza, Italy
- Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
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3
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Han JW, Shin EC. Investigating Human Liver Tissue-Resident Memory T Cells from the Perspectives of Gastroenterologists and Hepatologists. Gut Liver 2025; 19:161-170. [PMID: 40058791 PMCID: PMC11907256 DOI: 10.5009/gnl240366] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2024] [Revised: 09/18/2024] [Accepted: 09/22/2024] [Indexed: 03/15/2025] Open
Abstract
Liver tissue-resident memory T (TRM) cells play a pivotal role in hepatic immune responses. Their unique residence within liver sinusoids allow continuous antigen surveillance. In this review, we highlight the role of liver TRM cells in protective immunity and disease pathology. Comparisons between human and murine liver TRM cells reveal species-specific characteristics, suggesting the need for human-focused studies. One key finding is the involvement of liver TRM cells in viral hepatitis, where they can both control infection and contribute to liver damage. Liver TRM cells also exhibit dual roles in metabolic-associated steatotic liver disease, promoting inflammation and fibrosis while also contributing to fibrosis resolution. In autoimmune liver diseases, such as autoimmune hepatitis and primary sclerosing cholangitis, the presence of liver TRM cells correlates with disease severity. In this review, we underscore the importance of liver TRM cells in vaccine development, particularly vaccines against malaria. Future research should focus on the mechanisms governing TRM-cell formation, maintenance, and function, with the aim of supporting their protective roles while mitigating detrimental effects. Advancing our understanding of liver TRM cells will enhance our knowledge of liver immunology and inform novel therapeutic strategies for liver disease management.
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Affiliation(s)
- Ji Won Han
- The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, Korea
- Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Eui-Cheol Shin
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea
- The Center for Viral Immunology, Korea Virus Research Institute, Institute for Basic Science (IBS), Daejeon, Korea
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4
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Kremer KN, Khammash HA, Miranda AM, Rutt LN, Twardy SM, Anton PE, Campbell ML, Garza-Ortiz C, Orlicky DJ, Pelanda R, McCullough RL, Torres RM. Liver sinusoidal endothelial cells regulate the balance between hepatic immunosuppression and immunosurveillance. Front Immunol 2025; 15:1497788. [PMID: 39896805 PMCID: PMC11782242 DOI: 10.3389/fimmu.2024.1497788] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Accepted: 12/24/2024] [Indexed: 02/04/2025] Open
Abstract
As a metabolic center, the liver prevents inappropriate immune responses to abundant dietary antigens within the liver that could result in liver injury. This self-preservation mechanism can however decrease the efficiency of immunosurveillance of malignant cells by CD8 T cells. Hepatocellular carcinoma (HCC) is initiated by chronic viral infections, chronic alcohol consumption, and/or a fatty diet that leads to liver injury, fibrosis, and cirrhosis. HCC patients have high levels of dysfunctional and exhausted T cells, however, it is unclear which stage of HCC development contributes to T cell dysfunction. Repair of liver injury is initiated by interactions between injured hepatocytes and liver sinusoidal endothelial cells (LSEC), however, chronic injury can lead to fibrosis. Here, using a diethylnitrosamine/carbon tetrachloride (DEN/CCl4) mouse model of early HCC development, we demonstrate that chronic liver injury and fibrosis are sufficient to induce a CD8 T cell exhaustion signature with a corresponding increase in expression of immunosuppressive molecules on LSEC. We show that LSEC alter T cell function at various stages of T cell differentiation/activation. LSEC compete with dendritic cells presenting the same antigen to naïve CD8 T cells resulting in a unique T cell phenotype. Furthermore, LSEC abrogate killing of target cells, in an antigen-dependent manner, by previously activated effector CD8 T cells, and LSEC change the effector cell cytokine profile. Moreover, LSEC induce functional T cell exhaustion under low dose chronic stimulation conditions. Thus, LSEC critically regulate the balance between preventing/limiting liver injury and permitting sufficient tumor immunosurveillance with normal hepatic functions likely contributing to HCC development under conditions of chronic liver insult.
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Affiliation(s)
- Kimberly N. Kremer
- Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, United States
| | - Hadeel A. Khammash
- Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, United States
| | - Anjelica M. Miranda
- Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, United States
| | - Lauren N. Rutt
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO, United States
| | - Shannon M. Twardy
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO, United States
| | - Paige E. Anton
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO, United States
| | - Margaret L. Campbell
- Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, United States
| | - Christian Garza-Ortiz
- Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, United States
| | - David J. Orlicky
- Department of Pathology, University of Colorado School of Medicine, Aurora, CO, United States
| | - Roberta Pelanda
- Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, United States
| | - Rebecca L. McCullough
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO, United States
| | - Raul M. Torres
- Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, United States
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5
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Wohlleber D, Knolle PA. Tissue Determinants of Antiviral Immunity in the Liver. ZEITSCHRIFT FUR GASTROENTEROLOGIE 2025; 63:65-72. [PMID: 39793603 PMCID: PMC11723797 DOI: 10.1055/a-2365-3900] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/04/2024] [Accepted: 11/13/2024] [Indexed: 01/13/2025]
Abstract
The liver is an organ bearing important metabolic and immune functions. Hepatocytes are the main metabolically active cells of the liver and are the target of infection by hepatotropic viruses. Virus-specific CD8 T cells are essential for the control of hepatocyte infection with hepatotropic viruses but may be subject to local regulation of their effector function. Here, we review our current knowledge of the tissue determinants of antiviral immunity in the liver. Liver Sinusoidal Endothelial Cells (LSECs) not only allow through their fenestrations the access of circulating virus-specific CD8 T cells to engage in direct contact with infected hepatocytes without the need for extravasation but also cross-present viral antigens released from infected hepatocytes to these CD8 T cells. Two important features of LSECs and hepatocytes contribute to antiviral immune surveillance and liver failure. First, CD8 T cell immunity targeting LSECs leads to widespread endothelial cell death and results in sinusoidal microcirculation failure, causing fulminant viral hepatitis, whereas immune-mediated loss of hepatocytes is rapidly compensated by the regenerative capacity of the liver. Second, virus-infected hepatocytes support clearance of infection by responding to TNF, which is released from virus-specific CD8 T cells, with the selective induction of apoptosis. This increased sensitivity for TNF-induced death is caused by reduced mitochondrial resilience in virus-infected hepatocytes and may assist antiviral immunity in preferential targeting of virus-infected hepatocytes. Thus, hepatocytes and LSECs actively contribute to the outcome of antiviral CD8 T cell immunity in the liver. The knowledge of the mechanisms determining CD8 T cell control of hepatotropic viral infection will help to improve strategies to increase antiviral immune surveillance.
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Affiliation(s)
- Dirk Wohlleber
- Institute of Molecular Immunology, School of Medicine and Health, Technical University of Munich, Munich, Germany
| | - Percy A. Knolle
- Institute of Molecular Immunology, School of Life Science, Technical University of Munich, Munich, Germany
- German Center for Infection Research, Munich, Germany
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6
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Schäfer S, Gogiraju R, Rösch M, Kerstan Y, Beck L, Garbisch J, Saliba AE, Gisterå A, Hermanns HM, Boon L, Kastenmüller W, Schäfer K, Cochain C, Zernecke A. CD8 + T Cells Drive Plaque Smooth Muscle Cell Dedifferentiation in Experimental Atherosclerosis. Arterioscler Thromb Vasc Biol 2024; 44:1852-1872. [PMID: 38868941 DOI: 10.1161/atvbaha.123.320084] [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: 09/01/2023] [Accepted: 05/15/2024] [Indexed: 06/14/2024]
Abstract
BACKGROUND Atherosclerosis is driven by the infiltration of the arterial intima by diverse immune cells and smooth muscle cells (SMCs). CD8+ T cells promote lesion growth during atherosclerotic lesion development, but their role in advanced atherosclerosis is less clear. Here, we studied the role of CD8+ T cells and their effects on SMCs in established atherosclerosis. METHODS CD8+ T cells were depleted in (SMC reporter) low-density lipoprotein receptor-deficient (Ldlr-/-) mice with established atherosclerotic lesions. Atherosclerotic lesion formation was examined, and single-cell RNA sequencing of aortic SMCs and their progeny was performed. Additionally, coculture experiments with primary aortic SMCs and CD8+ T cells were conducted. RESULTS Although we could not detect differences in atherosclerotic lesion size, an increased plaque SMC content was noted in mice after CD8+ T-cell depletion. Single-cell RNA sequencing of aortic lineage-traced SMCs revealed contractile SMCs and a modulated SMC cluster, expressing macrophage- and osteoblast-related genes. CD8+ T-cell depletion was associated with an increased contractile but decreased macrophage and osteoblast-like gene signature in this modulated aortic SMC cluster. Conversely, exposure of isolated aortic SMCs to activated CD8+ T cells decreased the expression of genes indicative of a contractile SMC phenotype and induced a macrophage and osteoblast-like cell state. Notably, CD8+ T cells triggered calcium deposits in SMCs under osteogenic conditions. Mechanistically, we identified transcription factors highly expressed in modulated SMCs, including Runx1, to be induced by CD8+ T cells in cultured SMCs in an IFNγ (interferon-γ)-dependent manner. CONCLUSIONS We here uncovered CD8+ T cells to control the SMC phenotype in atherosclerosis. CD8+ T cells promote SMC dedifferentiation and drive SMCs to adopt features of macrophage-like and osteoblast-like, procalcifying cell phenotypes. Given the critical role of SMCs in atherosclerotic plaque stability, CD8+ T cells could thus be explored as therapeutic target cells during lesion progression.
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MESH Headings
- Animals
- CD8-Positive T-Lymphocytes/immunology
- CD8-Positive T-Lymphocytes/metabolism
- Myocytes, Smooth Muscle/pathology
- Myocytes, Smooth Muscle/metabolism
- Myocytes, Smooth Muscle/immunology
- Cell Dedifferentiation
- Plaque, Atherosclerotic
- Mice
- Disease Models, Animal
- Atherosclerosis/pathology
- Atherosclerosis/metabolism
- Atherosclerosis/genetics
- Atherosclerosis/immunology
- Muscle, Smooth, Vascular/pathology
- Muscle, Smooth, Vascular/metabolism
- Muscle, Smooth, Vascular/immunology
- Mice, Inbred C57BL
- Mice, Knockout
- Cells, Cultured
- Male
- Receptors, LDL/genetics
- Receptors, LDL/deficiency
- Phenotype
- Core Binding Factor Alpha 2 Subunit/genetics
- Core Binding Factor Alpha 2 Subunit/metabolism
- Aorta/pathology
- Aorta/immunology
- Aorta/metabolism
- Coculture Techniques
- Aortic Diseases/pathology
- Aortic Diseases/genetics
- Aortic Diseases/immunology
- Aortic Diseases/metabolism
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Affiliation(s)
- Sarah Schäfer
- Institute of Experimental Biomedicine (S.S., M.R., Y.K., L. Beck, J.G., C.C., A.Z.), University Hospital of Würzburg, Germany
| | - Rajinikanth Gogiraju
- Department of Cardiology, Cardiology I, University Medicine Mainz, Germany (R.G., K.S.)
| | - Melanie Rösch
- Institute of Experimental Biomedicine (S.S., M.R., Y.K., L. Beck, J.G., C.C., A.Z.), University Hospital of Würzburg, Germany
| | - Yvonne Kerstan
- Institute of Experimental Biomedicine (S.S., M.R., Y.K., L. Beck, J.G., C.C., A.Z.), University Hospital of Würzburg, Germany
| | - Lina Beck
- Institute of Experimental Biomedicine (S.S., M.R., Y.K., L. Beck, J.G., C.C., A.Z.), University Hospital of Würzburg, Germany
| | - Janine Garbisch
- Institute of Experimental Biomedicine (S.S., M.R., Y.K., L. Beck, J.G., C.C., A.Z.), University Hospital of Würzburg, Germany
| | - Antoine-Emmanuel Saliba
- Institute of Molecular Infection Biology Faculty of Medicine, University of Würzburg, Germany (A.-E.S.)
| | - Anton Gisterå
- Center for Molecular Medicine, Department of Medicine, Solna, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden (A.G.)
| | - Heike M Hermanns
- Medical Clinic II, Division of Hepatology (H.M.H.), University Hospital of Würzburg, Germany
| | | | | | - Katrin Schäfer
- Department of Cardiology, Cardiology I, University Medicine Mainz, Germany (R.G., K.S.)
| | - Clément Cochain
- Institute of Experimental Biomedicine (S.S., M.R., Y.K., L. Beck, J.G., C.C., A.Z.), University Hospital of Würzburg, Germany
| | - Alma Zernecke
- Institute of Experimental Biomedicine (S.S., M.R., Y.K., L. Beck, J.G., C.C., A.Z.), University Hospital of Würzburg, Germany
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7
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He Q, He W, Dong H, Guo Y, Yuan G, Shi X, Wang D, Lu F. Role of liver sinusoidal endothelial cell in metabolic dysfunction-associated fatty liver disease. Cell Commun Signal 2024; 22:346. [PMID: 38943171 PMCID: PMC11214243 DOI: 10.1186/s12964-024-01720-9] [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: 05/19/2024] [Accepted: 06/20/2024] [Indexed: 07/01/2024] Open
Abstract
Liver sinusoidal endothelial cells (LSECs) are highly specialized endothelial cells that represent the interface between blood cells on one side and hepatocytes on the other side. LSECs not only form a barrier within the hepatic sinus, but also play important physiological functions such as regulating hepatic vascular pressure, anti-inflammatory and anti-fibrotic. Pathologically, pathogenic factors can induce LSECs capillarization, that is, loss of fenestra and dysfunction, which are conducive to early steatosis, lay the foundation for the progression of metabolic dysfunction-associated fatty liver disease (MAFLD), and accelerate metabolic dysfunction-associated steatohepatitis (MASH) and liver fibrosis. The unique localization, phenotype, and function of LSECs make them potential candidates for reducing liver injury, inflammation, and preventing or reversing fibrosis in the future.
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Affiliation(s)
- Qiongyao He
- Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Wu He
- Division of Cardiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
- Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan, 430030, China
| | - Hui Dong
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Yujin Guo
- Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Gang Yuan
- Department of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Xiaoli Shi
- Department of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Dingkun Wang
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, 430030, China.
| | - Fuer Lu
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, 430030, China.
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8
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Sun Y, Tong H, Chu X, Li Y, Zhang J, Ding Y, Zhang S, Gui X, Chen C, Xu M, Li Z, Gardiner EE, Andrews RK, Zeng L, Xu K, Qiao J. Notch1 regulates hepatic thrombopoietin production. Blood 2024; 143:2778-2790. [PMID: 38603632 DOI: 10.1182/blood.2023023559] [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: 12/13/2023] [Revised: 03/22/2024] [Accepted: 04/05/2024] [Indexed: 04/13/2024] Open
Abstract
ABSTRACT Notch signaling regulates cell-fate decisions in several developmental processes and cell functions. However, the role of Notch in hepatic thrombopoietin (TPO) production remains unclear. We noted thrombocytopenia in mice with hepatic Notch1 deficiency and so investigated TPO production and other features of platelets in these mice. We found that the liver ultrastructure and hepatocyte function were comparable between control and Notch1-deficient mice. However, the Notch1-deficient mice had significantly lower plasma TPO and hepatic TPO messenger RNA levels, concomitant with lower numbers of platelets and impaired megakaryocyte differentiation and maturation, which were rescued by addition of exogenous TPO. Additionally, JAK2/STAT3 phosphorylation was significantly inhibited in Notch1-deficient hepatocytes, consistent with the RNA-sequencing analysis. JAK2/STAT3 phosphorylation and TPO production was also impaired in cultured Notch1-deficient hepatocytes after treatment with desialylated platelets. Consistently, hepatocyte-specific Notch1 deletion inhibited JAK2/STAT3 phosphorylation and hepatic TPO production induced by administration of desialylated platelets in vivo. Interestingly, Notch1 deficiency downregulated the expression of HES5 but not HES1. Moreover, desialylated platelets promoted the binding of HES5 to JAK2/STAT3, leading to JAK2/STAT3 phosphorylation and pathway activation in hepatocytes. Hepatocyte Ashwell-Morell receptor (AMR), a heterodimer of asialoglycoprotein receptor 1 [ASGR1] and ASGR2, physically associates with Notch1, and inhibition of AMR impaired Notch1 signaling activation and hepatic TPO production. Furthermore, blockage of Delta-like 4 on desialylated platelets inhibited hepatocyte Notch1 activation and HES5 expression, JAK2/STAT3 phosphorylation, and subsequent TPO production. In conclusion, our study identifies a novel regulatory role of Notch1 in hepatic TPO production, indicating that it might be a target for modulating TPO level.
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Affiliation(s)
- Yueyue Sun
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
- Key Laboratory of Bone Marrow Stem Cell, Xuzhou, China
| | - Huan Tong
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
- Key Laboratory of Bone Marrow Stem Cell, Xuzhou, China
| | - Xiang Chu
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
- Key Laboratory of Bone Marrow Stem Cell, Xuzhou, China
| | - Yingying Li
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
- Key Laboratory of Bone Marrow Stem Cell, Xuzhou, China
| | - Jie Zhang
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
- Key Laboratory of Bone Marrow Stem Cell, Xuzhou, China
| | - Yangyang Ding
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
- Key Laboratory of Bone Marrow Stem Cell, Xuzhou, China
| | - Sixuan Zhang
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
- Key Laboratory of Bone Marrow Stem Cell, Xuzhou, China
| | - Xiang Gui
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
- Key Laboratory of Bone Marrow Stem Cell, Xuzhou, China
| | - Chong Chen
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
- Key Laboratory of Bone Marrow Stem Cell, Xuzhou, China
| | - Mengdi Xu
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
- Key Laboratory of Bone Marrow Stem Cell, Xuzhou, China
| | - Zhenyu Li
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
- Key Laboratory of Bone Marrow Stem Cell, Xuzhou, China
| | - Elizabeth E Gardiner
- Division of Genome Science and Cancer, John Curtin School of Medical Research, Australian National University, Canberra, Australia
| | - Robert K Andrews
- Division of Genome Science and Cancer, John Curtin School of Medical Research, Australian National University, Canberra, Australia
| | - Lingyu Zeng
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
- Key Laboratory of Bone Marrow Stem Cell, Xuzhou, China
| | - Kailin Xu
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
- Key Laboratory of Bone Marrow Stem Cell, Xuzhou, China
| | - Jianlin Qiao
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
- Key Laboratory of Bone Marrow Stem Cell, Xuzhou, China
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9
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Tian SP, Ge JY, Song YM, Yu XQ, Chen WH, Chen YY, Ye D, Zheng YW. A novel efficient strategy to generate liver sinusoidal endothelial cells from human pluripotent stem cells. Sci Rep 2024; 14:13831. [PMID: 38879647 PMCID: PMC11180100 DOI: 10.1038/s41598-024-64195-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Accepted: 06/06/2024] [Indexed: 06/19/2024] Open
Abstract
Liver sinusoidal endothelial cells (LSECs) are highly specialized endothelial cells (ECs) that play an important role in liver development and regeneration. Additionally, it is involved in various pathological processes, including steatosis, inflammation, fibrosis and hepatocellular carcinoma. However, the rapid dedifferentiation of LSECs after culture greatly limits their use in vitro modeling for biomedical applications. In this study, we developed a highly efficient protocol to induce LSEC-like cells from human induced pluripotent stem cells (hiPSCs) in only 8 days. Using single-cell transcriptomic analysis, we identified several novel LSEC-specific markers, such as EPAS1, LIFR, and NID1, as well as several previously revealed markers, such as CLEC4M, CLEC1B, CRHBP and FCN3. These LSEC markers are specifically expressed in our LSEC-like cells. Furthermore, hiPSC-derived cells expressed LSEC-specific proteins and exhibited LSEC-related functions, such as the uptake of acetylated low density lipoprotein (ac-LDL) and immune complex endocytosis. Overall, this study confirmed that our novel protocol allowed hiPSCs to rapidly acquire an LSEC-like phenotype and function in vitro. The ability to generate LSECs efficiently and rapidly may help to more precisely mimic liver development and disease progression in a liver-specific multicellular microenvironment, offering new insights into the development of novel therapeutic strategies.
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Affiliation(s)
- Shang-Ping Tian
- Guangdong Provincial Key Laboratory of Large Animal Models for Biomedicine, and South China Institute of Large Animal Models for Biomedicine, School of Pharmacy and Food Engineering, Wuyi University, Jiangmen, Guangdong, China
| | - Jian-Yun Ge
- Guangdong Provincial Key Laboratory of Large Animal Models for Biomedicine, and South China Institute of Large Animal Models for Biomedicine, School of Pharmacy and Food Engineering, Wuyi University, Jiangmen, Guangdong, China
| | - Yu-Mu Song
- Guangdong Provincial Key Laboratory of Large Animal Models for Biomedicine, and South China Institute of Large Animal Models for Biomedicine, School of Pharmacy and Food Engineering, Wuyi University, Jiangmen, Guangdong, China
| | - Xiao-Qing Yu
- Guangdong Provincial Key Laboratory of Large Animal Models for Biomedicine, and South China Institute of Large Animal Models for Biomedicine, School of Pharmacy and Food Engineering, Wuyi University, Jiangmen, Guangdong, China
| | - Wen-Hao Chen
- Guangdong Provincial Key Laboratory of Large Animal Models for Biomedicine, and South China Institute of Large Animal Models for Biomedicine, School of Pharmacy and Food Engineering, Wuyi University, Jiangmen, Guangdong, China
| | - Yu-Ying Chen
- Guangdong Provincial Key Laboratory of Large Animal Models for Biomedicine, and South China Institute of Large Animal Models for Biomedicine, School of Pharmacy and Food Engineering, Wuyi University, Jiangmen, Guangdong, China
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, China
| | - Di Ye
- Guangdong Provincial Key Laboratory of Large Animal Models for Biomedicine, and South China Institute of Large Animal Models for Biomedicine, School of Pharmacy and Food Engineering, Wuyi University, Jiangmen, Guangdong, China
| | - Yun-Wen Zheng
- Guangdong Provincial Key Laboratory of Large Animal Models for Biomedicine, and South China Institute of Large Animal Models for Biomedicine, School of Pharmacy and Food Engineering, Wuyi University, Jiangmen, Guangdong, China.
- Institute of Regenerative Medicine, and Department of Dermatology, Affiliated Hospital of Jiangsu University, Jiangsu University, Zhenjiang, Jiangsu, China.
- Department of Medical and Life Sciences, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba, Japan.
- Institute of Medical Science, Center for Stem Cell Biology and Regenerative Medicine, The University of Tokyo, Tokyo, Japan.
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10
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Trinchese G, Cimmino F, Catapano A, Cavaliere G, Mollica MP. Mitochondria: the gatekeepers between metabolism and immunity. Front Immunol 2024; 15:1334006. [PMID: 38464536 PMCID: PMC10920337 DOI: 10.3389/fimmu.2024.1334006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Accepted: 02/08/2024] [Indexed: 03/12/2024] Open
Abstract
Metabolism and immunity are crucial monitors of the whole-body homeodynamics. All cells require energy to perform their basic functions. One of the most important metabolic skills of the cell is the ability to optimally adapt metabolism according to demand or availability, known as metabolic flexibility. The immune cells, first line of host defense that circulate in the body and migrate between tissues, need to function also in environments in which nutrients are not always available. The resilience of immune cells consists precisely in their high adaptive capacity, a challenge that arises especially in the framework of sustained immune responses. Pubmed and Scopus databases were consulted to construct the extensive background explored in this review, from the Kennedy and Lehninger studies on mitochondrial biochemistry of the 1950s to the most recent findings on immunometabolism. In detail, we first focus on how metabolic reconfiguration influences the action steps of the immune system and modulates immune cell fate and function. Then, we highlighted the evidence for considering mitochondria, besides conventional cellular energy suppliers, as the powerhouses of immunometabolism. Finally, we explored the main immunometabolic hubs in the organism emphasizing in them the reciprocal impact between metabolic and immune components in both physiological and pathological conditions.
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Affiliation(s)
| | - Fabiano Cimmino
- Department of Biology, University of Naples Federico II, Naples, Italy
| | - Angela Catapano
- Department of Biology, University of Naples Federico II, Naples, Italy
| | - Gina Cavaliere
- Department of Pharmaceutical Sciences, University of Perugia, Perugia, Italy
| | - Maria Pina Mollica
- Department of Biology, University of Naples Federico II, Naples, Italy
- Task Force on Microbiome Studies, University of Naples Federico II, Naples, Italy
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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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Kusumoputro S, Au C, Lam KH, Park N, Hyun A, Kusumoputro E, Wang X, Xia T. Liver-Targeting Nanoplatforms for the Induction of Immune Tolerance. NANOMATERIALS (BASEL, SWITZERLAND) 2023; 14:67. [PMID: 38202522 PMCID: PMC10780512 DOI: 10.3390/nano14010067] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Revised: 12/14/2023] [Accepted: 12/21/2023] [Indexed: 01/12/2024]
Abstract
Liver-targeting nanoparticles have emerged as a promising platform for the induction of immune tolerance by taking advantage of the liver's unique tolerogenic properties and nanoparticles' physicochemical flexibility. Such an approach provides a versatile solution to the treatment of a diversity of immunologic diseases. In this review, we begin by assessing the design parameters integral to cell-specific targeting and the tolerogenic induction of nanoplatforms engineered to target the four critical immunogenic hepatic cells, including liver sinusoidal epithelial cells (LSECs), Kupffer cells (KCs), hepatic stellate cells (HSCs), and hepatocytes. We also include an overview of multiple therapeutic strategies in which nanoparticles are being studied to treat many allergies and autoimmune disorders. Finally, we explore the challenges of using nanoparticles in this field while highlighting future avenues to expand the therapeutic utility of liver-targeting nanoparticles in autoimmune processes.
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Affiliation(s)
- Sydney Kusumoputro
- Department of Medicine, Drexel University College of Medicine, Philadelphia, PA 19129, USA; (S.K.); (N.P.)
- Department of Ecology and Evolutionary Biology, University of California, Los Angeles, CA 90095, USA
| | - Christian Au
- Department of Bioengineering, University of California, Los Angeles, CA 90095, USA;
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90007, USA;
| | - Katie H. Lam
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90007, USA;
- Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CA 90095, USA
| | - Nathaniel Park
- Department of Medicine, Drexel University College of Medicine, Philadelphia, PA 19129, USA; (S.K.); (N.P.)
| | - Austin Hyun
- Department of Medicine, Lake Erie College of Osteopathic Medicine, Bradenton, FL 34211, USA;
- Department of Integrative Biology and Physiology, University of California, Los Angeles, CA 90095, USA
| | - Emily Kusumoputro
- Department of Evolution, Ecology, and Organismal Biology, University of California, Riverside, CA 92521, USA;
| | - Xiang Wang
- Division of NanoMedicine, Department of Medicine, University of California, Los Angeles, CA 90095, USA
- California NanoSystems Institute, University of California, Los Angeles, CA 90095, USA
| | - Tian Xia
- Division of NanoMedicine, Department of Medicine, University of California, Los Angeles, CA 90095, USA
- California NanoSystems Institute, University of California, Los Angeles, CA 90095, USA
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13
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Jacobs R, Dogbey MD, Mnyandu N, Neves K, Barth S, Arbuthnot P, Maepa MB. AAV Immunotoxicity: Implications in Anti-HBV Gene Therapy. Microorganisms 2023; 11:2985. [PMID: 38138129 PMCID: PMC10745739 DOI: 10.3390/microorganisms11122985] [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: 11/03/2023] [Revised: 11/30/2023] [Accepted: 12/11/2023] [Indexed: 12/24/2023] Open
Abstract
Hepatitis B virus (HBV) has afflicted humankind for decades and there is still no treatment that can clear the infection. The development of recombinant adeno-associated virus (rAAV)-based gene therapy for HBV infection has become important in recent years and research has made exciting leaps. Initial studies, mainly using mouse models, showed that rAAVs are non-toxic and induce minimal immune responses. However, several later studies demonstrated rAAV toxicity, which is inextricably associated with immunogenicity. This is a major setback for the progression of rAAV-based therapies toward clinical application. Research aimed at understanding the mechanisms behind rAAV immunity and toxicity has contributed significantly to the inception of approaches to overcoming these challenges. The target tissue, the features of the vector, and the vector dose are some of the determinants of AAV toxicity, with the latter being associated with the most severe adverse events. This review discusses our current understanding of rAAV immunogenicity, toxicity, and approaches to overcoming these hurdles. How this information and current knowledge about HBV biology and immunity can be harnessed in the efforts to design safe and effective anti-HBV rAAVs is discussed.
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Affiliation(s)
- Ridhwaanah Jacobs
- Wits/SAMRC Antiviral Gene Therapy Research Unit, Infectious Diseases and Oncology Research Institute (IDORI), Faculty of Health Sciences, University of the Witwatersrand, Parktown 2193, South Africa
| | - Makafui Dennis Dogbey
- Medical Biotechnology and Immunotherapy Research Unit, Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town 7700, South Africa; (M.D.D.)
| | - Njabulo Mnyandu
- Wits/SAMRC Antiviral Gene Therapy Research Unit, Infectious Diseases and Oncology Research Institute (IDORI), Faculty of Health Sciences, University of the Witwatersrand, Parktown 2193, South Africa
| | - Keila Neves
- Wits/SAMRC Antiviral Gene Therapy Research Unit, Infectious Diseases and Oncology Research Institute (IDORI), Faculty of Health Sciences, University of the Witwatersrand, Parktown 2193, South Africa
| | - Stefan Barth
- Medical Biotechnology and Immunotherapy Research Unit, Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town 7700, South Africa; (M.D.D.)
- South African Research Chair in Cancer Biotechnology, Department of Integrative Biomedical Sciences, Faculty of Health Sciences, University of Cape Town, Cape Town 7700, South Africa
| | - Patrick Arbuthnot
- Wits/SAMRC Antiviral Gene Therapy Research Unit, Infectious Diseases and Oncology Research Institute (IDORI), Faculty of Health Sciences, University of the Witwatersrand, Parktown 2193, South Africa
| | - Mohube Betty Maepa
- Wits/SAMRC Antiviral Gene Therapy Research Unit, Infectious Diseases and Oncology Research Institute (IDORI), Faculty of Health Sciences, University of the Witwatersrand, Parktown 2193, South Africa
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14
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Bousso P, Grandjean CL. Immunomodulation under the lens of real-time in vivo imaging. Eur J Immunol 2023; 53:e2249921. [PMID: 37051691 DOI: 10.1002/eji.202249921] [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: 07/27/2022] [Revised: 11/16/2022] [Accepted: 04/11/2023] [Indexed: 04/14/2023]
Abstract
Modulation of cells and molecules of the immune system not only represents a major opportunity to treat a variety of diseases including infections, cancer, autoimmune, and inflammatory disorders but could also help understand the intricacies of immune responses. A detailed mechanistic understanding of how a specific immune intervention may provide clinical benefit is essential for the rational design of efficient immunomodulators. Visualizing the impact of immunomodulation in real-time and in vivo has emerged as an important approach to achieve this goal. In this review, we aim to illustrate how multiphoton intravital imaging has helped clarify the mode of action of immunomodulatory strategies such as antibodies or cell therapies. We also discuss how optogenetics combined with imaging will further help manipulate and precisely understand immunomodulatory pathways. Combined with other single-cell technologies, in vivo dynamic imaging has therefore a major potential for guiding preclinical development of immunomodulatory drugs.
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Affiliation(s)
- Philippe Bousso
- Dynamics of Immune Responses Unit, Institut Pasteur, INSERM U1223, Université de Paris Cité, Paris, France
| | - Capucine L Grandjean
- Dynamics of Immune Responses Unit, Institut Pasteur, INSERM U1223, Université de Paris Cité, Paris, France
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15
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Bayerl F, Bejarano DA, Bertacchi G, Doffin AC, Gobbini E, Hubert M, Li L, Meiser P, Pedde AM, Posch W, Rupp L, Schlitzer A, Schmitz M, Schraml BU, Uderhardt S, Valladeau-Guilemond J, Wilflingseder D, Zaderer V, Böttcher JP. Guidelines for visualization and analysis of DC in tissues using multiparameter fluorescence microscopy imaging methods. Eur J Immunol 2023; 53:e2249923. [PMID: 36623939 DOI: 10.1002/eji.202249923] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Revised: 11/07/2022] [Accepted: 11/14/2022] [Indexed: 01/11/2023]
Abstract
This article is part of the Dendritic Cell Guidelines article series, which provides a collection of state-of-the-art protocols for the preparation, phenotype analysis by flow cytometry, generation, fluorescence microscopy, and functional characterization of mouse and human dendritic cells (DC) from lymphoid organs and various non-lymphoid tissues. Here, we provide detailed procedures for a variety of multiparameter fluorescence microscopy imaging methods to explore the spatial organization of DC in tissues and to dissect how DC migrate, communicate, and mediate their multiple functional roles in immunity in a variety of tissue settings. The protocols presented here entail approaches to study DC dynamics and T cell cross-talk by intravital microscopy, large-scale visualization, identification, and quantitative analysis of DC subsets and their functions by multiparameter fluorescence microscopy of fixed tissue sections, and an approach to study DC interactions with tissue cells in a 3D cell culture model. While all protocols were written by experienced scientists who routinely use them in their work, this article was also peer-reviewed by leading experts and approved by all co-authors, making it an essential resource for basic and clinical DC immunologists.
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Affiliation(s)
- Felix Bayerl
- Institute of Molecular Immunology, School of Medicine, Klinikum Rechts der Isar, Technical University of Munich (TUM), Ismaninger Str. 22, Munich, Germany
| | - David A Bejarano
- Quantitative Systems Biology, Life and Medical Sciences (LIMES) Institute, University of Bonn, Germany
| | - Giulia Bertacchi
- Institute of Hygiene and Medical Microbiology, Medical University of Innsbruck, Innsbruck, Austria
| | - Anne-Claire Doffin
- Cancer Research Center Lyon, UMR INSERM 1052 CNRS 5286, Centre Léon Bérard, 28 rue Laennec, Lyon, France
| | - Elisa Gobbini
- Cancer Research Center Lyon, UMR INSERM 1052 CNRS 5286, Centre Léon Bérard, 28 rue Laennec, Lyon, France
| | - Margaux Hubert
- Cancer Research Center Lyon, UMR INSERM 1052 CNRS 5286, Centre Léon Bérard, 28 rue Laennec, Lyon, France
| | - Lijian Li
- Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum für Immuntherapie (DZI), Friedrich-Alexander University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany
- Exploratory Research Unit, Optical Imaging Centre Erlangen (OICE), Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany
| | - Philippa Meiser
- Institute of Molecular Immunology, School of Medicine, Klinikum Rechts der Isar, Technical University of Munich (TUM), Ismaninger Str. 22, Munich, Germany
| | - Anna-Marie Pedde
- Institute of Molecular Immunology, School of Medicine, Klinikum Rechts der Isar, Technical University of Munich (TUM), Ismaninger Str. 22, Munich, Germany
| | - Wilfried Posch
- Institute of Hygiene and Medical Microbiology, Medical University of Innsbruck, Innsbruck, Austria
| | - Luise Rupp
- Institute of Immunology, Faculty of Medicine Carl Gustav Carus, TU Dresden, Dresden, Germany
| | - Andreas Schlitzer
- Quantitative Systems Biology, Life and Medical Sciences (LIMES) Institute, University of Bonn, Germany
| | - Marc Schmitz
- Institute of Immunology, Faculty of Medicine Carl Gustav Carus, TU Dresden, Dresden, Germany
- National Center for Tumor Diseases (NCT), Partner Site Dresden, Dresden, Germany
- German Cancer Consortium (DKTK), Partner Site Dresden, and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Barbara U Schraml
- Walter-Brendel-Centre of Experimental Medicine, University Hospital, LMU Munich, Planegg-Martinsried, Germany
- Biomedical Center, Institute for Cardiovascular Physiology and Pathophysiology, Faculty of Medicine, LMU Munich, Planegg-Martinsried, Germany
| | - Stefan Uderhardt
- Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum für Immuntherapie (DZI), Friedrich-Alexander University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany
- Exploratory Research Unit, Optical Imaging Centre Erlangen (OICE), Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany
| | - Jenny Valladeau-Guilemond
- Cancer Research Center Lyon, UMR INSERM 1052 CNRS 5286, Centre Léon Bérard, 28 rue Laennec, Lyon, France
| | - Doris Wilflingseder
- Institute of Hygiene and Medical Microbiology, Medical University of Innsbruck, Innsbruck, Austria
| | - Viktoria Zaderer
- Institute of Hygiene and Medical Microbiology, Medical University of Innsbruck, Innsbruck, Austria
| | - Jan P Böttcher
- Institute of Molecular Immunology, School of Medicine, Klinikum Rechts der Isar, Technical University of Munich (TUM), Ismaninger Str. 22, Munich, Germany
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16
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Matsuo S, Nabekura T, Matsuda K, Shibuya K, Shibuya A. DNAM-1 Immunoreceptor Protects Mice from Concanavalin A-Induced Acute Liver Injury by Reducing Neutrophil Infiltration. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2023; 211:954-963. [PMID: 37522739 DOI: 10.4049/jimmunol.2200705] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Accepted: 07/13/2023] [Indexed: 08/01/2023]
Abstract
DNAX accessory molecule-1 (DNAM-1; CD226) is an activating immunoreceptor on T cells and NK cells. The interaction of DNAM-1 with its ligand CD155 expressed on hematopoietic and nonhematopoietic cells plays an important role in innate and adaptive immune responses. In this study, we investigated the role of the DNAM-1-CD155 axis in the pathogenesis of T cell-mediated Con A-induced acute liver injury. Unexpectedly, DNAM-1-deficient (Cd226-/-) mice exhibited more severe acute liver injury and higher concentrations of IL-6 and TNF-α than did wild-type (WT) mice after Con A injection. We found that a larger number of neutrophils infiltrated into the liver of Cd226-/- mice compared with WT mice after Con A injection. Depletion of neutrophils ameliorated liver injury and decreased IL-6 and TNF-α in Cd226-/- mice after Con A injection, suggesting that neutrophils exacerbate the liver injury in Cd226-/- mice. Hepatocytes produced more significant amounts of CXCL1, a chemoattractant for neutrophils, in Cd226-/- mice than in WT mice after Con A injection. In the coculture of hepatocytes with liver lymphocytes, either DNAM-1 deficiency in liver lymphocytes or CD155 deficiency in hepatocytes promoted CXCL1 production by hepatocytes. These results suggest that the interaction of DNAM-1 with CD155 inhibits CXCL1 production by hepatocytes, leading to ameliorating acute liver injury.
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Affiliation(s)
- Soichi Matsuo
- Department of Immunology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
- Doctoral Program in Medical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Tsukasa Nabekura
- Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance, University of Tsukuba, Tsukuba, Ibaraki, Japan
- R&D Center for Innovative Drug Discovery, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Kenshiro Matsuda
- Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance, University of Tsukuba, Tsukuba, Ibaraki, Japan
- R&D Center for Innovative Drug Discovery, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Kazuko Shibuya
- Department of Immunology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
- R&D Center for Innovative Drug Discovery, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Akira Shibuya
- Department of Immunology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
- Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance, University of Tsukuba, Tsukuba, Ibaraki, Japan
- R&D Center for Innovative Drug Discovery, University of Tsukuba, Tsukuba, Ibaraki, Japan
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Hassert M, Arumugam S, Harty JT. Memory CD8+ T cell-mediated protection against liver-stage malaria. Immunol Rev 2023; 316:84-103. [PMID: 37014087 PMCID: PMC10524177 DOI: 10.1111/imr.13202] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2023] [Revised: 03/09/2023] [Accepted: 03/21/2023] [Indexed: 04/05/2023]
Abstract
Nearly half of the world's population is at risk of malaria, a disease caused by the protozoan parasite Plasmodium, which is estimated to cause more than 240,000,000 infections and kill more than 600,000 people annually. The emergence of Plasmodia resistant to chemoprophylactic treatment highlights the urgency to develop more effective vaccines. In this regard, whole sporozoite vaccination approaches in murine models and human challenge studies have provided substantial insight into the immune correlates of protection from malaria. From these studies, CD8+ T cells have come to the forefront, being identified as critical for vaccine-mediated liver-stage immunity that can prevent the establishment of the symptomatic blood stages and subsequent transmission of infection. However, the unique biological characteristics required for CD8+ T cell protection from liver-stage malaria dictate that more work must be done to design effective vaccines. In this review, we will highlight a subset of studies that reveal basic aspects of memory CD8+ T cell-mediated protection from liver-stage malaria infection.
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Affiliation(s)
- Mariah Hassert
- Department of Pathology, University of Iowa- Carver College of Medicine, Iowa City, IA, USA
| | - Sahaana Arumugam
- Department of Pathology, University of Iowa- Carver College of Medicine, Iowa City, IA, USA
- Medical Scientist Training Program, University of Iowa- Carver College of Medicine, Iowa City, IA, USA
- Interdisciplinary Graduate Program in Immunology, University of Iowa- Carver College of Medicine, Iowa City, IA, USA
| | - John T. Harty
- Department of Pathology, University of Iowa- Carver College of Medicine, Iowa City, IA, USA
- Interdisciplinary Graduate Program in Immunology, University of Iowa- Carver College of Medicine, Iowa City, IA, USA
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18
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Wu RY, Wang BC, Wang K, Xia F, Zhang ZY, Wan JF, Zhang Z. Immunotherapy and tumor mutational burden in cancer patients with liver metastases: A meta and real word cohort analysis. Front Oncol 2023; 12:994276. [PMID: 36741738 PMCID: PMC9893030 DOI: 10.3389/fonc.2022.994276] [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: 07/14/2022] [Accepted: 12/20/2022] [Indexed: 01/20/2023] Open
Abstract
Background The predictive effects of liver metastases for immune-checkpoint inhibitors (ICIs) and the relationship between tumor mutational burden (TMB) and liver metastases (LM) remain unclear. Methods A systematic review and meta-analysis were conducted to explore the heterogeneity of ICIs efficacy between patients with or without LM. A pan-cancer cohort of 1,661 patients who received ICIs was downloaded and analyzed to assess the association between TMB and LM. Results Of 21053 studies identified in our search, eight single-arm studies and 24 randomized controlled trials were included. Overall, 17957 patients with advanced or metastatic cancers (4805 patients (26.8%) with LM and 13151 patients (73.2%) without LM) were enrolled. The pooled objective response rate (ORR) was 8.5% (95% CI 4%-13%) in the LM group versus 21% (95% CI 16%-21%) in the non-LM group. The pooled hazard ratio (HR) for death was 0.85 (95% CI 0.80-0.90) in the LM group treated with ICIs compared with the standard of care. In patients without LM who were treated with ICIs, the pooled HR for death was 0.78 (95% CI 0.73-0.82) compared with the standard of care. The difference in efficacy between patients with or without LM treated with ICIs was significant (p=0.04). Pan-cancer analysis revealed that the TMB-high rate was 10.8% in liver metastatic lesions versus 21.4% in other metastatic lesions (p=0.004). In addition, TMB was also significantly associated with OS as a binary cutoff (p=0.05) and was an independent prognostic variable (HR=0.98, P=0.047) as a continuous variable in patients with LM. Conclusions In patients with LM, the efficacy of immunotherapy was attenuated, but TMB-high could predict better survival outcomes.
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Affiliation(s)
- Rui-Yan Wu
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China,Shanghai Clinical Research Center for Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China,Shanghai Key Laboratory of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Bi-Cheng Wang
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Kun Wang
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China,Shanghai Clinical Research Center for Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China,Shanghai Key Laboratory of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Fan Xia
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China,Shanghai Clinical Research Center for Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China,Shanghai Key Laboratory of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Zhi-Yuan Zhang
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China,Shanghai Clinical Research Center for Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China,Shanghai Key Laboratory of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Jue-Feng Wan
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China,Shanghai Clinical Research Center for Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China,Shanghai Key Laboratory of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China,*Correspondence: Zhen Zhang, ; Jue-Feng Wan,
| | - Zhen Zhang
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China,Shanghai Clinical Research Center for Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China,Shanghai Key Laboratory of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China,*Correspondence: Zhen Zhang, ; Jue-Feng Wan,
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19
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Chen X, Liu X, Jiang Y, Xia N, Liu C, Luo W. Abnormally primed CD8 T cells: The Achilles' heel of CHB. Front Immunol 2023; 14:1106700. [PMID: 36936922 PMCID: PMC10014547 DOI: 10.3389/fimmu.2023.1106700] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Accepted: 02/20/2023] [Indexed: 03/05/2023] Open
Abstract
Chronic hepatitis B virus (HBV) infection continues to be a significant public health challenge, and more than 250 million people around world are infected with HBV. The clearance of HBV with virus-specific CD8 T cells is critical for a functional cure. However, naïve HBV-specific CD8 T cells are heavily hindered during the priming process, and this phenomenon is closely related to abnormal cell and signal interactions in the complex immune microenvironment. Here, we briefly summarize the recent progress in understanding the abnormal priming of HBV-specific CD8 T cells and some corresponding immunotherapies to facilitate their functional recovery, which provides a novel perspective for the design and development of immunotherapy for chronic HBV infection (CHB). Finally, we also highlight the balance between viral clearance and pathological liver injury induced by CD8 T-cell activation that should be carefully considered during drug development.
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Affiliation(s)
- Xiaoqing Chen
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, Fujian, China
| | - Xue Liu
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, Fujian, China
| | - Yichao Jiang
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, Fujian, China
| | - Ningshao Xia
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, Fujian, China
- Xiang An Biomedicine Laboratory, Xiamen, Fujian, China
- The Research Unit of Frontier Technology of Structural Vaccinology, Chinese Academy of Medical Sciences, Xiamen, Fujian, China
| | - Chao Liu
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, Fujian, China
- State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian, China
- *Correspondence: Wenxin Luo, ; Chao Liu,
| | - Wenxin Luo
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, Fujian, China
- Xiang An Biomedicine Laboratory, Xiamen, Fujian, China
- *Correspondence: Wenxin Luo, ; Chao Liu,
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20
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The Tumor Microenvironment of Hepatocellular Carcinoma: Untying an Intricate Immunological Network. Cancers (Basel) 2022; 14:cancers14246151. [PMID: 36551635 PMCID: PMC9776867 DOI: 10.3390/cancers14246151] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 12/06/2022] [Accepted: 12/11/2022] [Indexed: 12/23/2022] Open
Abstract
HCC, the most prevalent form of primary liver cancer, is prototypically an inflammation-driven cancer developing after years of inflammatory insults. Consequently, the hepatic microenvironment is a site of complex immunological activities. Moreover, the tolerogenic nature of the liver can act as a barrier to anti-tumor immunity, fostering cancer progression and resistance to immunotherapies based on immune checkpoint inhibitors (ICB). In addition to being a site of primary carcinogenesis, many cancer types have high tropism for the liver, and patients diagnosed with liver metastasis have a dismal prognosis. Therefore, understanding the immunological networks characterizing the tumor microenvironment (TME) of HCC will deepen our understanding of liver immunity, and it will underpin the dominant mechanisms controlling both spontaneous and therapy-induced anti-tumor immune responses. Herein, we discuss the contributions of the cellular and molecular components of the liver immune contexture during HCC onset and progression by underscoring how the balance between antagonistic immune responses can recast the properties of the TME and the response to ICB.
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21
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Liu N, Bauer M, Press AT. The immunological function of CXCR2 in the liver during sepsis. J Inflamm (Lond) 2022; 19:23. [DOI: 10.1186/s12950-022-00321-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Accepted: 11/15/2022] [Indexed: 12/02/2022] Open
Abstract
Abstract
Background
The chemokine receptor CXCR2 and its ligands, especially CXCL8, are crucial mediators for the progression of liver inflammation and liver failure in sepsis. Neutrophils have the highest CXCR2 expression in mice and humans, and their activation via CXCL8 facilitates their migration to the inflamed liver for the clearance of the pathogens and, in turn, the inflammation.
Main body
In sepsis, the inflammatory insult causes extensive neutrophil migration to the liver that overwhelms the immune response. To compensate for the strong receptor activation, CXCR2 desensitizes, incapacitating the immune cells to efficiently clear pathogens, causing further life-threatening liver damage and uncontrolled pathogen spread.
Conclusion
CXCR2 function during infection strongly depends on the expressing cell type. It signals pro- and anti-inflammatory effects that may prompt novel cell-type-specific CXCR2-directed therapeutics.
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22
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Pallett LJ, Maini MK. Liver-resident memory T cells: life in lockdown. Semin Immunopathol 2022; 44:813-825. [PMID: 35482059 PMCID: PMC9708784 DOI: 10.1007/s00281-022-00932-w] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Accepted: 03/17/2022] [Indexed: 12/15/2022]
Abstract
A subset of memory T cells has been identified in the liver with a tissue-resident profile and the capacity for long-term 'lockdown'. Here we review how they are retained in, and adapted to, the hepatic microenvironment, including its unique anatomical features and metabolic challenges. We describe potential interactions with other local cell types and the need for a better understanding of this complex bidirectional crosstalk. Pathogen or tumour antigen-specific tissue-resident memory T cells (TRM) can provide rapid frontline immune surveillance; we review the evidence for this in hepatotropic infections of major worldwide importance like hepatitis B and malaria and in liver cancers like hepatocellular carcinoma. Conversely, TRM can be triggered by pro-inflammatory and metabolic signals to mediate bystander tissue damage, with an emerging role in a number of liver pathologies. We discuss the need for liver sampling to gain a window into these compartmentalised T cells, allowing more accurate disease monitoring and future locally targeted immunotherapies.
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Affiliation(s)
- Laura J Pallett
- Institute of Immunity & Transplantation, Division of Infection & Immunity, UCL, Pears Building, Rowland Hill St, London, NW3 2PP, UK.
| | - Mala K Maini
- Institute of Immunity & Transplantation, Division of Infection & Immunity, UCL, Pears Building, Rowland Hill St, London, NW3 2PP, UK.
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23
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Hoogerland JA, Staels B, Dombrowicz D. Immune-metabolic interactions in homeostasis and the progression to NASH. Trends Endocrinol Metab 2022; 33:690-709. [PMID: 35961913 DOI: 10.1016/j.tem.2022.07.001] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Revised: 07/09/2022] [Accepted: 07/12/2022] [Indexed: 12/16/2022]
Abstract
The incidence of non-alcoholic fatty liver disease (NAFLD) has increased significantly over the past two decades. NAFLD ranges from simple steatosis (NAFL) to nonalcoholic steatohepatitis (NASH) and predisposes to fibrosis and hepatocellular carcinoma (HCC). The importance of the immune system in hepatic physiology and in the progression of NAFLD is increasingly recognized. At homeostasis, the liver participates in immune defense against pathogens and in tolerance of gut-derived microbial compounds. Hepatic immune cells also respond to metabolic stimuli and have a role in NAFLD progression to NASH. In this review, we discuss how metabolic perturbations affect immune cell phenotype and function in NAFL and NASH, and then focus on the role of immune cells in liver homeostasis and in the development of NASH.
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Affiliation(s)
- Joanne A Hoogerland
- Univeristy of Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, F-59000 Lille, France
| | - Bart Staels
- Univeristy of Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, F-59000 Lille, France
| | - David Dombrowicz
- Univeristy of Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, F-59000 Lille, France.
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24
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Lu Y, Ma S, Ding W, Sun P, Zhou Q, Duan Y, Sartorius K. Resident Immune Cells of the Liver in the Tumor Microenvironment. Front Oncol 2022; 12:931995. [PMID: 35965506 PMCID: PMC9365660 DOI: 10.3389/fonc.2022.931995] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Accepted: 06/13/2022] [Indexed: 12/30/2022] Open
Abstract
The liver is a central immunomodulator that ensures a homeostatic balance between protection and immunotolerance. A hallmark of hepatocellular carcinoma (HCC) is the deregulation of this tightly controlled immunological network. Immune response in the liver involves a complex interplay between resident innate, innate, and adaptive immune cells. The immune response in the liver is modulated by its continuous exposure to toxic molecules and microorganisms that requires a degree of immune tolerance to protect normal tissue from damage. In HCC pathogenesis, immune cells must balance a dual role that includes the elimination of malignant cells, as well as the repair of damaged liver tissue to maintain homeostasis. Immune response in the innate and adaptive immune systems extends to the cross-talk and interaction involving immune-regulating non-hematopoietic cells, myeloid immune cells, and lymphoid immune cells. In this review, we discuss the different immune responses of resident immune cells in the tumor microenvironment. Current FDA-approved targeted therapies, including immunotherapy options, have produced modest results to date for the treatment of advanced HCC. Although immunotherapy therapy to date has demonstrated its potential efficacy, immune cell pathways need to be better understood. In this review article, we summarize the roles of specific resident immune cell subsets and their cross-talk subversion in HCC pathogenesis, with a view to identifying potential new biomarkers and therapy options.
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Affiliation(s)
- Yunjie Lu
- The Third Affiliated Hospital of Soochow University, Chanozhou, China
| | - Shiying Ma
- The Third Affiliated Hospital of Soochow University, Chanozhou, China
| | - Wei Ding
- Department of General Surgery, Wujin Hospital Affiliated to Jiangsu University, Changzhou, China
| | - Pengcheng Sun
- The Third Affiliated Hospital of Soochow University, Chanozhou, China
| | - Qi Zhou
- The Third Affiliated Hospital of Soochow University, Chanozhou, China
| | - Yunfei Duan
- The Third Affiliated Hospital of Soochow University, Chanozhou, China
| | - Kurt Sartorius
- Hepatitis Diversity Research Unit, School of Internal Medicine, University of the Witwatersrand, Johannesburg, South Africa
- Africa Hepatopancreatobiliary Cancer Consortium (AHPBCC), Mayo Clinic, Jacksonville, FL, United States
- University of Kwazulu-Natal Gastrointestinal Cancer Research Unit (UKZN/GICRC), Durban, South Africa
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25
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Wang Y, Wang J. Intravital Imaging of Inflammatory Response in Liver Disease. Front Cell Dev Biol 2022; 10:922041. [PMID: 35837329 PMCID: PMC9274191 DOI: 10.3389/fcell.2022.922041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2022] [Accepted: 05/16/2022] [Indexed: 11/17/2022] Open
Abstract
The healthy liver requires a strictly controlled crosstalk between immune and nonimmune cells to maintain its function and homeostasis. A well-conditioned immune system can effectively recognize and clear noxious stimuli by a self-limited, small-scale inflammatory response. This regulated inflammatory process enables the liver to cope with daily microbial exposure and metabolic stress, which is beneficial for hepatic self-renewal and tissue remodeling. However, the failure to clear noxious stimuli or dysregulation of immune response can lead to uncontrolled liver inflammation, liver dysfunction, and severe liver disease. Numerous highly dynamic circulating immune cells and sessile resident immune and parenchymal cells interact and communicate with each other in an incredibly complex way to regulate the inflammatory response in both healthy and diseased liver. Intravital imaging is a powerful tool to visualize individual cells in vivo and has been widely used for dissecting the behavior and interactions between various cell types in the complex architecture of the liver. Here, we summarize some new findings obtained with the use of intravital imaging, which enhances our understanding of the complexity of immune cell behavior, cell–cell interaction, and spatial organization during the physiological and pathological liver inflammatory response.
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26
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Gottwick C, Carambia A, Herkel J. Harnessing the liver to induce antigen-specific immune tolerance. Semin Immunopathol 2022; 44:475-484. [PMID: 35513495 PMCID: PMC9256566 DOI: 10.1007/s00281-022-00942-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Accepted: 04/20/2022] [Indexed: 12/17/2022]
Abstract
Autoimmune diseases develop when the adaptive immune system attacks the body’s own antigens leading to tissue damage. At least 80 different conditions are believed to have an autoimmune aetiology, including rheumatoid arthritis, type I diabetes, multiple sclerosis or systemic lupus erythematosus. Collectively, autoimmune diseases are a leading cause of severe health impairment along with substantial socioeconomic costs. Current treatments are mostly symptomatic and non-specific, and it is typically not possible to cure these diseases. Thus, the development of more causative treatments that suppress only the pathogenic immune responses, but spare general immunity is of great biomedical interest. The liver offers considerable potential for development of such antigen-specific immunotherapies, as it has a distinct physiological capacity to induce immune tolerance. Indeed, the liver has been shown to specifically suppress autoimmune responses to organ allografts co-transplanted with the liver or to autoantigens that were transferred to the liver. Liver tolerance is established by a unique microenvironment that facilitates interactions between liver-resident antigen-presenting cells and lymphocytes passing by in the low blood flow within the hepatic sinusoids. Here, we summarise current concepts and mechanisms of liver immune tolerance, and review present approaches to harness liver tolerance for antigen-specific immunotherapy.
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Affiliation(s)
- Cornelia Gottwick
- First Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
| | - Antonella Carambia
- First Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
| | - Johannes Herkel
- First Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
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27
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Hall BM, Verma ND, Tran GT, Hodgkinson SJ. Transplant Tolerance, Not Only Clonal Deletion. Front Immunol 2022; 13:810798. [PMID: 35529847 PMCID: PMC9069565 DOI: 10.3389/fimmu.2022.810798] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2021] [Accepted: 02/23/2022] [Indexed: 11/13/2022] Open
Abstract
The quest to understand how allogeneic transplanted tissue is not rejected and how tolerance is induced led to fundamental concepts in immunology. First, we review the research that led to the Clonal Deletion theory in the late 1950s that has since dominated the field of immunology and transplantation. At that time many basic mechanisms of immune response were unknown, including the role of lymphocytes and T cells in rejection. These original observations are reassessed by considering T regulatory cells that are produced by thymus of neonates to prevent autoimmunity. Second, we review "operational tolerance" induced in adult rodents and larger animals such as pigs. This can occur spontaneously especially with liver allografts, but also can develop after short courses of a variety of rejection inhibiting therapies. Over time these animals develop alloantigen specific tolerance to the graft but retain the capacity to reject third-party grafts. These animals have a "split tolerance" as peripheral lymphocytes from these animals respond to donor alloantigen in graft versus host assays and in mixed lymphocyte cultures, indicating there is no clonal deletion. Investigation of this phenomenon excludes many mechanisms, including anti-donor antibody blocking rejection as well as anti-idiotypic responses mediated by antibody or T cells. This split tolerance is transferred to a second immune-depleted host by T cells that retain the capacity to effect rejection of third-party grafts by the same host. Third, we review research on alloantigen specific inhibitory T cells that led to the first identification of the CD4+CD25+T regulatory cell. The key role of T cell derived cytokines, other than IL-2, in promoting survival and expansion of antigen specific T regulatory cells that mediate transplant tolerance is reviewed. The precise methods for inducing and diagnosing operational tolerance remain to be defined, but antigen specific T regulatory cells are key mediators.
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Affiliation(s)
- Bruce M. Hall
- Immune Tolerance Laboratory, School of Medicine, University of New South Wales (UNSW) Sydney, Ingham Institute, and Renal Service and Multiple Sclerosis Clinic, Liverpool Hospital, Liverpool, NSW, Australia
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28
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Dalod M, Scheu S. Dendritic cell functions in vivo: a user's guide to current and next generation mutant mouse models. Eur J Immunol 2022; 52:1712-1749. [PMID: 35099816 DOI: 10.1002/eji.202149513] [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: 11/19/2021] [Accepted: 01/14/2022] [Indexed: 11/11/2022]
Abstract
Dendritic cells (DCs) do not just excel in antigen presentation. They orchestrate information transfer from innate to adaptive immunity, by sensing and integrating a variety of danger signals, and translating them to naïve T cells, to mount specifically tailored immune responses. This is accomplished by distinct DC types specialized in different functions and because each DC is functionally plastic, assuming different activation states depending on the input signals received. Mouse models hold the key to untangle this complexity and determine which DC types and activation states contribute to which functions. Here, we aim to provide comprehensive information for selecting the most appropriate mutant mouse strains to address specific research questions on DCs, considering three in vivo experimental approaches: (i) interrogating the roles of DC types through their depletion; (ii) determining the underlying mechanisms by specific genetic manipulations; (iii) deciphering the spatiotemporal dynamics of DC responses. We summarize the advantages, caveats, suggested use and perspectives for a variety of mutant mouse strains, discussing in more detail the most widely used or accurate models. Finally, we discuss innovative strategies to improve targeting specificity, for the next generation mutant mouse models, and briefly address how humanized mouse models can accelerate translation into the clinic. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Marc Dalod
- CNRS, Inserm, Aix Marseille Univ, Centre d'Immunologie de Marseille-Luminy (CIML), Turing Center for Living Systems, Marseille, France
| | - Stefanie Scheu
- Institute of Medical Microbiology and Hospital Hygiene, University of Düsseldorf, Düsseldorf, Germany
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Abstract
Hepatitis B virus (HBV) is a non-cytopathic, hepatotropic virus with the potential to cause a persistent infection, ultimately leading to cirrhosis and hepatocellular carcinoma. Over the past four decades, the basic principles of HBV gene expression and replication as well as the viral and host determinants governing infection outcome have been largely uncovered. Whereas HBV appears to induce little or no innate immune activation, the adaptive immune response mediates both viral clearance as well as liver disease. Here, we review our current knowledge on the immunobiology and pathogenesis of HBV infection, focusing in particular on the role of CD8+ T cells and on several recent breakthroughs that challenge current dogmas. For example, we now trust that HBV integration into the host genome often serves as a relevant source of hepatitis B surface antigen (HBsAg) expression during chronic infection, possibly triggering dysfunctional T cell responses and favouring detrimental immunopathology. Further, the unique haemodynamics and anatomy of the liver - and the changes they frequently endure during disease progression to liver fibrosis and cirrhosis - profoundly influence T cell priming, differentiation and function. We also discuss why therapeutic approaches that limit the intrahepatic inflammatory processes triggered by HBV-specific T cells might be surprisingly beneficial for patients with chronic infection.
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30
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De Simone G, Andreata F, Bleriot C, Fumagalli V, Laura C, Garcia-Manteiga JM, Di Lucia P, Gilotto S, Ficht X, De Ponti FF, Bono EB, Giustini L, Ambrosi G, Mainetti M, Zordan P, Bénéchet AP, Ravà M, Chakarov S, Moalli F, Bajenoff M, Guidotti LG, Ginhoux F, Iannacone M. Identification of a Kupffer cell subset capable of reverting the T cell dysfunction induced by hepatocellular priming. Immunity 2021; 54:2089-2100.e8. [PMID: 34469774 PMCID: PMC8459394 DOI: 10.1016/j.immuni.2021.05.005] [Citation(s) in RCA: 103] [Impact Index Per Article: 25.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Revised: 03/13/2021] [Accepted: 05/05/2021] [Indexed: 12/13/2022]
Abstract
Kupffer cells (KCs) are highly abundant, intravascular, liver-resident macrophages known for their scavenger and phagocytic functions. KCs can also present antigens to CD8+ T cells and promote either tolerance or effector differentiation, but the mechanisms underlying these discrepant outcomes are poorly understood. Here, we used a mouse model of hepatitis B virus (HBV) infection, in which HBV-specific naive CD8+ T cells recognizing hepatocellular antigens are driven into a state of immune dysfunction, to identify a subset of KCs (referred to as KC2) that cross-presents hepatocellular antigens upon interleukin-2 (IL-2) administration, thus improving the antiviral function of T cells. Removing MHC-I from all KCs, including KC2, or selectively depleting KC2 impaired the capacity of IL-2 to revert the T cell dysfunction induced by intrahepatic priming. In summary, by sensing IL-2 and cross-presenting hepatocellular antigens, KC2 overcome the tolerogenic potential of the hepatic microenvironment, suggesting new strategies for boosting hepatic T cell immunity.
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Affiliation(s)
- Giorgia De Simone
- Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy; Vita-Salute San Raffaele University, 20132 Milan, Italy
| | - Francesco Andreata
- Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
| | - Camille Bleriot
- Singapore Immunology Network (SIgN), Agency for Science, Technology & Research (A(∗)STAR), 8A Biomedical Grove, Immunos Building #3-4, Biopolis, Singapore 138648
| | - Valeria Fumagalli
- Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy; Vita-Salute San Raffaele University, 20132 Milan, Italy
| | - Chiara Laura
- Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy; Vita-Salute San Raffaele University, 20132 Milan, Italy; Center for Omics Sciences, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
| | | | - Pietro Di Lucia
- Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
| | - Stefano Gilotto
- Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy; Center for Omics Sciences, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
| | - Xenia Ficht
- Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
| | - Federico F De Ponti
- Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
| | - Elisa B Bono
- Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
| | - Leonardo Giustini
- Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
| | - Gioia Ambrosi
- Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
| | - Marta Mainetti
- Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
| | - Paola Zordan
- Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
| | - Alexandre P Bénéchet
- Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
| | - Micol Ravà
- Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
| | - Svetoslav Chakarov
- Singapore Immunology Network (SIgN), Agency for Science, Technology & Research (A(∗)STAR), 8A Biomedical Grove, Immunos Building #3-4, Biopolis, Singapore 138648
| | - Federica Moalli
- Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
| | - Marc Bajenoff
- Aix Marseille University, CNRS, INSERM, CIML, Marseille 13288, France
| | - Luca G Guidotti
- Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy; Vita-Salute San Raffaele University, 20132 Milan, Italy
| | - Florent Ginhoux
- Singapore Immunology Network (SIgN), Agency for Science, Technology & Research (A(∗)STAR), 8A Biomedical Grove, Immunos Building #3-4, Biopolis, Singapore 138648; Shanghai Institute of Immunology, Shanghai JiaoTong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, China; Translational Immunology Institute, SingHealth Duke-NUS Academic Medical Centre, 169856, Singapore
| | - Matteo Iannacone
- Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy; Vita-Salute San Raffaele University, 20132 Milan, Italy; Experimental Imaging Centre, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
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Vacani-Martins N, Meuser-Batista M, dos Santos CDLP, Hasslocher-Moreno AM, Henriques-Pons A. The Liver and the Hepatic Immune Response in Trypanosoma cruzi Infection, a Historical and Updated View. Pathogens 2021; 10:pathogens10091074. [PMID: 34578107 PMCID: PMC8465576 DOI: 10.3390/pathogens10091074] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Revised: 08/05/2021] [Accepted: 08/11/2021] [Indexed: 12/12/2022] Open
Abstract
Chagas disease was described more than a century ago and, despite great efforts to understand the underlying mechanisms that lead to cardiac and digestive manifestations in chronic patients, much remains to be clarified. The disease is found beyond Latin America, including Japan, the USA, France, Spain, and Australia, and is caused by the protozoan Trypanosoma cruzi. Dr. Carlos Chagas described Chagas disease in 1909 in Brazil, and hepatomegaly was among the clinical signs observed. Currently, hepatomegaly is cited in most papers published which either study acutely infected patients or experimental models, and we know that the parasite can infect multiple cell types in the liver, especially Kupffer cells and dendritic cells. Moreover, liver damage is more pronounced in cases of oral infection, which is mainly found in the Amazon region. However, the importance of liver involvement, including the hepatic immune response, in disease progression does not receive much attention. In this review, we present the very first paper published approaching the liver's participation in the infection, as well as subsequent papers published in the last century, up to and including our recently published results. We propose that, after infection, activated peripheral T lymphocytes reach the liver and induce a shift to a pro-inflammatory ambient environment. Thus, there is an immunological integration and cooperation between peripheral and hepatic immunity, contributing to disease control.
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Affiliation(s)
- Natalia Vacani-Martins
- Laboratório de Inovações em Terapias, Ensino e Bioprodutos, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro 21041-361, Brazil; (N.V.-M.); (C.d.L.P.d.S.)
| | - Marcelo Meuser-Batista
- Depto de Anatomia Patológica e Citopatologia, Instituto Fernandes Figueira, Fundação Oswaldo Cruz, Rio de Janeiro 22250-020, Brazil;
| | - Carina de Lima Pereira dos Santos
- Laboratório de Inovações em Terapias, Ensino e Bioprodutos, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro 21041-361, Brazil; (N.V.-M.); (C.d.L.P.d.S.)
| | | | - Andrea Henriques-Pons
- Laboratório de Inovações em Terapias, Ensino e Bioprodutos, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro 21041-361, Brazil; (N.V.-M.); (C.d.L.P.d.S.)
- Correspondence:
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Wang T, Yeh MM, Avigan MI, Pelosof L, Feldman GM. Deciphering the Dynamic Complexities of the Liver Microenvironment - Toward a Better Understanding of Immune-Mediated liver Injury Caused by Immune Checkpoint Inhibitors (ILICI). AAPS JOURNAL 2021; 23:99. [PMID: 34401948 DOI: 10.1208/s12248-021-00629-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Accepted: 07/26/2021] [Indexed: 11/30/2022]
Abstract
Immune checkpoint inhibitors (ICIs) represent a promising therapy for many types of cancer. However, only a portion of patients respond to this therapy and some patients develop clinically significant immune-mediated liver injury caused by immune checkpoint inhibitors (ILICI), an immune-related adverse event (irAE) that may require the interruption or termination of treatment and administration of systemic corticosteroids or other immunosuppressive agents. Although the incidence of ILICI is lower with monotherapy, the surge in combining ICIs with chemotherapy, targeted therapy, and combination of different ICIs has led to an increase in the incidence and severity of ILICI - a major challenge for development of effective and safe ICI therapy. In this review, we highlight the importance and contribution of the liver microenvironment to ILICI by focusing on the emerging roles of resident liver cells in modulating immune homeostasis and hepatocyte regeneration, two important decisive factors that dictate the initiation, progression, and recovery from ILICI. Based on the proposed contribution of the liver microenvironment on ICILI, we discuss the clinical characteristics of ILICI in patients with preexisting liver diseases, as well as the challenges of identifying prognostic biomarkers to guide the clinical management of severe ILICI. A better understanding of the liver microenvironment may lead to novel strategies and identification of novel biomarkers for effective management of ILICI.
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Affiliation(s)
- Tao Wang
- Office of Biotechnology Products, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, 10903 New Hampshire Ave, Silver Spring, Maryland, 20993, USA.
| | - Matthew M Yeh
- Department of Laboratory Medicine and Pathology, University of Washington School of Medicine, Seattle, Washington, 98195, USA
| | - Mark I Avigan
- Office of Surveillance and Epidemiology, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, 20993, USA
| | - Lorraine Pelosof
- Office of New Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, 20993, USA
| | - Gerald M Feldman
- Office of Biotechnology Products, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, 10903 New Hampshire Ave, Silver Spring, Maryland, 20993, USA
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Sernoskie SC, Jee A, Uetrecht JP. The Emerging Role of the Innate Immune Response in Idiosyncratic Drug Reactions. Pharmacol Rev 2021; 73:861-896. [PMID: 34016669 DOI: 10.1124/pharmrev.120.000090] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Idiosyncratic drug reactions (IDRs) range from relatively common, mild reactions to rarer, potentially life-threatening adverse effects that pose significant risks to both human health and successful drug discovery. Most frequently, IDRs target the liver, skin, and blood or bone marrow. Clinical data indicate that most IDRs are mediated by an adaptive immune response against drug-modified proteins, formed when chemically reactive species of a drug bind to self-proteins, making them appear foreign to the immune system. Although much emphasis has been placed on characterizing the clinical presentation of IDRs and noting implicated drugs, limited research has focused on the mechanisms preceding the manifestations of these severe responses. Therefore, we propose that to address the knowledge gap between drug administration and onset of a severe IDR, more research is required to understand IDR-initiating mechanisms; namely, the role of the innate immune response. In this review, we outline the immune processes involved from neoantigen formation to the result of the formation of the immunologic synapse and suggest that this framework be applied to IDR research. Using four drugs associated with severe IDRs as examples (amoxicillin, amodiaquine, clozapine, and nevirapine), we also summarize clinical and animal model data that are supportive of an early innate immune response. Finally, we discuss how understanding the early steps in innate immune activation in the development of an adaptive IDR will be fundamental in risk assessment during drug development. SIGNIFICANCE STATEMENT: Although there is some understanding that certain adaptive immune mechanisms are involved in the development of idiosyncratic drug reactions, the early phase of these immune responses remains largely uncharacterized. The presented framework refocuses the investigation of IDR pathogenesis from severe clinical manifestations to the initiating innate immune mechanisms that, in contrast, may be quite mild or clinically silent. A comprehensive understanding of these early influences on IDR onset is crucial for accurate risk prediction, IDR prevention, and therapeutic intervention.
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Affiliation(s)
- Samantha Christine Sernoskie
- Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy (S.C.S., J.P.U.), and Department of Pharmacology and Toxicology, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada (A.J., J.P.U.)
| | - Alison Jee
- Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy (S.C.S., J.P.U.), and Department of Pharmacology and Toxicology, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada (A.J., J.P.U.)
| | - Jack Paul Uetrecht
- Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy (S.C.S., J.P.U.), and Department of Pharmacology and Toxicology, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada (A.J., J.P.U.)
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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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Innate immunity in hepatitis B and D virus infection: consequences for viral persistence, inflammation, and T cell recognition. Semin Immunopathol 2021; 43:535-548. [PMID: 34019142 PMCID: PMC8443521 DOI: 10.1007/s00281-021-00864-x] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Accepted: 04/30/2021] [Indexed: 12/16/2022]
Abstract
Chronic infections with human hepatitis viruses continue to be a major health burden worldwide. Despite the availability of an effective prophylactic vaccine against the hepatitis B virus (HBV) and of antiviral agents efficiently suppressing HBV replication, more than 250 million people are currently chronically infected with this hepatotropic DNA virus, and resolution of chronic hepatitis B (CHB) is rarely achieved. Moreover, coinfection with the hepatitis D virus (HDV), a human RNA satellite virus requiring the envelope proteins of HBV for productive viral spreading, substantially aggravates the disease course of CHB. The molecular mechanisms by which these viruses interact with each other and with the intrinsic innate responses of the hepatocytes are not fully understood. While HBV appears to avoid innate immune recognition, HDV elicits a strong enhancement of innate responses. Notwithstanding, such induction does not hamper HDV replication but contributes to liver inflammation and pathogenesis. Intriguingly, HDV appears to influence the ability of T cells to recognize infected hepatocytes by boosting antigen presentation. This review focuses on current knowledge regarding how these viruses can shape and counteract the intrinsic innate responses of the hepatocytes, thus affecting the immune system and pathogenesis. Understanding the distinct strategies of persistence that HBV and HDV have evolved is central for advancing the development of curative therapies.
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Karakas D, Xu M, Ni H. GPIbα is the driving force of hepatic thrombopoietin generation. Res Pract Thromb Haemost 2021; 5:e12506. [PMID: 33977209 PMCID: PMC8105161 DOI: 10.1002/rth2.12506] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Revised: 02/19/2021] [Accepted: 02/26/2021] [Indexed: 12/25/2022] Open
Abstract
Thrombopoietin (TPO), a glycoprotein hormone produced predominantly in the liver, plays important roles in the hematopoietic stem cell (HSC) niche, and is essential for megakaryopoiesis and platelet generation. Long-standing understanding proposes that TPO is constitutively produced by hepatocytes, and levels are fine-tuned through platelet and megakaryocyte internalization/degradation via the c-Mpl receptor. However, in immune thrombocytopenia (ITP) and several other diseases, TPO levels are inconsistent with this theory. Recent studies showed that platelets, besides their TPO clearance, can induce TPO production in the liver. Our group also accidentally discovered that platelet glycoprotein (GP) Ibα is required for platelet-mediated TPO generation, which is underscored in both GPIbα-/- mice and patients with Bernard-Soulier syndrome. This review will introduce platelet versatilities and several new findings in hemostasis and platelet consumption but focus on its roles in TPO regulation. The implications of these new discoveries in hematopoiesis and the HSC niche, particularly in ITP, will be discussed.
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Affiliation(s)
- Danielle Karakas
- Department of Laboratory Medicine and PathobiologyUniversity of TorontoTorontoONCanada
- Toronto Platelet Immunobiology GroupTorontoONCanada
- Department of Laboratory MedicineKeenan Research Centre for Biomedical ScienceSt. Michael’s HospitalTorontoONCanada
| | - Miao Xu
- Department of HematologyQilu HospitalCheeloo College of MedicineShandong UniversityJinanChina
| | - Heyu Ni
- Department of Laboratory Medicine and PathobiologyUniversity of TorontoTorontoONCanada
- Toronto Platelet Immunobiology GroupTorontoONCanada
- Department of Laboratory MedicineKeenan Research Centre for Biomedical ScienceSt. Michael’s HospitalTorontoONCanada
- Canadian Blood Services Centre for InnovationTorontoONCanada
- Department of MedicineUniversity of TorontoTorontoONCanada
- Department of PhysiologyUniversity of TorontoTorontoONCanada
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Qin J, Lovelace MD, Mitchell AJ, de Koning-Ward T, Grau GE, Pai S. Perivascular macrophages create an intravascular niche for CD8 + T cell localisation prior to the onset of fatal experimental cerebral malaria. Clin Transl Immunology 2021; 10:e1273. [PMID: 33854773 PMCID: PMC8026342 DOI: 10.1002/cti2.1273] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Revised: 02/03/2021] [Accepted: 03/14/2021] [Indexed: 12/12/2022] Open
Abstract
Objectives The immunologic events that build up to the fatal neurological stage of experimental cerebral malaria (ECM) are incompletely understood. Here, we dissect immune cell behaviour occurring in the central nervous system (CNS) when Plasmodium berghei ANKA (PbA)‐infected mice show only minor clinical signs. Methods A 2‐photon intravital microscopy (2P‐IVM) brain imaging model was used to study the spatiotemporal context of early immunological events in situ during ECM. Results Early in the disease course, antigen‐specific CD8+ T cells came in contact and arrested on the endothelium of post‐capillary venules. CD8+ T cells typically adhered adjacent to, or were in the near vicinity of, perivascular macrophages (PVMs) that line post‐capillary venules. Closer examination revealed that CD8+ T cells crawled along the inner vessel wall towards PVMs that lay on the abluminal side of large post‐capillary venules. ‘Activity hotspots’ in large post‐capillary venules were characterised by T‐cell localisation, activated morphology and clustering of PVM, increased abutting of post‐capillary venules by PVM and augmented monocyte accumulation. In the later stages of infection, when mice exhibited neurological signs, intravascular CD8+ T cells increased in number and changed their behaviour, actively crawling along the endothelium and displaying frequent, short‐term interactions with the inner vessel wall at hotspots. Conclusion Our study suggests an active interaction between PVM and CD8+ T cells occurs across the blood–brain barrier (BBB) in early ECM, which may be the initiating event in the inflammatory cascade leading to BBB alteration and neuropathology.
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Affiliation(s)
| | - Michael D Lovelace
- Applied Neurosciences Program Peter Duncan Neurosciences Research Unit St Vincent's Centre for Applied Medical Research Sydney NSW Australia.,UNSW St Vincent's Clinical School Faculty of Medicine UNSW Sydney Sydney NSW Australia
| | - Andrew J Mitchell
- Materials Characterisation and Fabrication Platform Department of Chemical Engineering University of Melbourne Parkville VIC Australia
| | | | - Georges Er Grau
- Vascular Immunology Unit Discipline of Pathology School of Medical Sciences University of Sydney Camperdown NSW Australia
| | - Saparna Pai
- Centre for Molecular Therapeutics Australian Institute of Tropical Health and Medicine James Cook University Cairns QLD Australia.,Faculty of Medicine and Health University of Sydney Sydney NSW Australia
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Mechanisms of anti-GPIbα antibody-induced thrombocytopenia in mice. Blood 2021; 135:2292-2301. [PMID: 32157300 DOI: 10.1182/blood.2019003770] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2019] [Accepted: 02/18/2020] [Indexed: 12/11/2022] Open
Abstract
Immune thrombocytopenia (ITP) is an acquired bleeding disorder characterized by antibody-mediated platelet destruction. Different mechanisms have been suggested to explain accelerated platelet clearance and impaired thrombopoiesis, but the pathophysiology of ITP has yet to be fully delineated. In this study, we tested 2 mouse models of immune-mediated thrombocytopenia using the rat anti-mouse GPIbα monoclonal antibody 5A7, generated in our laboratory. After a single IV administration of high-dose (2 mg/kg) 5A7, opsonized platelets were rapidly cleared from the circulation into the spleen and liver; this was associated with rapid upregulation of thrombopoietin (TPO) messenger RNA. In contrast, subcutaneous administration of low-dose 5A7 (0.08-0.16 mg/kg) every 3 days gradually lowered the platelet count; in this case, opsonized platelets were observed only in the spleen, and TPO levels remained unaltered. Interestingly, in both models, the 5A7 antibody was found on the surface of, as well as internalized to, bone marrow megakaryocytes. Consequently, platelets generated in the chronic phase of repeated subcutaneous 5A7 administration model showed reduced GPIbα membrane expression on their surface. Our findings indicate that evaluation of platelet surface GPIbα relative to platelet size may be a useful marker to support the diagnosis of anti-GPIbα antibody-induced ITP.
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Fernandez-Ruiz D, de Menezes MN, Holz LE, Ghilas S, Heath WR, Beattie L. Harnessing liver-resident memory T cells for protection against malaria. Expert Rev Vaccines 2021; 20:127-141. [PMID: 33501877 DOI: 10.1080/14760584.2021.1881485] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
INTRODUCTION Tissue-resident memory T cells (TRM cells) are powerful mediators of protracted adaptive immunity to infection in peripheral organs. Harnessing TRM cells through vaccination hence promises unprecedented potential for protection against infection. A paramount example of this is malaria, a major infectious disease for which immunity through traditional vaccination strategies remains challenging. Liver TRM cells appear to be highly protective against malaria, and recent developments in our knowledge of the biology of these cells have defined promising, novel strategies for their induction. AREAS COVERED Here, we describe the path that led to the discovery of TRM cells and discuss the importance of liver TRM cells in immunity against Plasmodium spp. infection; we summarize current knowledge on TRM cell biology and discuss the current state and potential of TRM-based vaccination against malaria. EXPERT OPINION TRM based vaccination has emerged as a promising means to achieve efficient protection against malaria. Recent advances provide a solid basis for continuing the development of this area of research. Deeper understanding of the mechanisms that mediate TRM formation and maintenance and identification of immunogenic and protective target epitopes suitable for human vaccination remain the main challenges for translation of these discoveries.
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Affiliation(s)
- Daniel Fernandez-Ruiz
- Dept. Of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, the University of Melbourne, Melbourne, Vic, Australia.,Australian Research Council Centre of Excellence in Advanced Molecular Imaging, University of Melbourne, Melbourne,Vic, Australia
| | - Maria N de Menezes
- Dept. Of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, the University of Melbourne, Melbourne, Vic, Australia
| | - Lauren E Holz
- Dept. Of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, the University of Melbourne, Melbourne, Vic, Australia.,Australian Research Council Centre of Excellence in Advanced Molecular Imaging, University of Melbourne, Melbourne,Vic, Australia
| | - Sonia Ghilas
- Dept. Of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, the University of Melbourne, Melbourne, Vic, Australia.,Australian Research Council Centre of Excellence in Advanced Molecular Imaging, University of Melbourne, Melbourne,Vic, Australia
| | - William R Heath
- Dept. Of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, the University of Melbourne, Melbourne, Vic, Australia.,Australian Research Council Centre of Excellence in Advanced Molecular Imaging, University of Melbourne, Melbourne,Vic, Australia
| | - Lynette Beattie
- Dept. Of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, the University of Melbourne, Melbourne, Vic, Australia.,Australian Research Council Centre of Excellence in Advanced Molecular Imaging, University of Melbourne, Melbourne,Vic, Australia
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Liver metastasis restrains immunotherapy efficacy via macrophage-mediated T cell elimination. Nat Med 2021; 27:152-164. [PMID: 33398162 PMCID: PMC8095049 DOI: 10.1038/s41591-020-1131-x] [Citation(s) in RCA: 609] [Impact Index Per Article: 152.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Accepted: 10/13/2020] [Indexed: 02/08/2023]
Abstract
Metastasis is the primary cause of cancer mortality, and cancer frequently metastasizes to the liver. It is not clear whether liver immune tolerance mechanisms contribute to cancer outcomes. We report that liver metastases diminish immunotherapy efficacy systemically in patients and preclinical models. Patients with liver metastases derive limited benefit from immunotherapy independent of other established biomarkers of response. In multiple mouse models, we show that liver metastases siphon activated CD8+ T cells from systemic circulation. Within the liver, activated antigen-specific Fas+CD8+ T cells undergo apoptosis following their interaction with FasL+CD11b+F4/80+ monocyte-derived macrophages. Consequently, liver metastases create a systemic immune desert in preclinical models. Similarly, patients with liver metastases have reduced peripheral T cell numbers and diminished tumoral T cell diversity and function. In preclinical models, liver-directed radiotherapy eliminates immunosuppressive hepatic macrophages, increases hepatic T cell survival and reduces hepatic siphoning of T cells. Thus, liver metastases co-opt host peripheral tolerance mechanisms to cause acquired immunotherapy resistance through CD8+ T cell deletion, and the combination of liver-directed radiotherapy and immunotherapy could promote systemic antitumor immunity.
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Resident Memory T Cells and Their Role within the Liver. Int J Mol Sci 2020; 21:ijms21228565. [PMID: 33202970 PMCID: PMC7696659 DOI: 10.3390/ijms21228565] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Revised: 10/29/2020] [Accepted: 11/11/2020] [Indexed: 01/17/2023] Open
Abstract
Immunological memory is fundamental to maintain immunity against re-invading pathogens. It is the basis for prolonged protection induced by vaccines and can be mediated by humoral or cellular responses-the latter largely mediated by T cells. Memory T cells belong to different subsets with specialized functions and distributions within the body. They can be broadly separated into circulating memory cells, which pace the entire body through the lymphatics and blood, and tissue-resident memory T (TRM) cells, which are constrained to peripheral tissues. Retained in the tissues where they form, TRM cells provide a frontline defense against reinfection. Here, we review this population of cells with specific attention to the liver, where TRM cells have been found to protect against infections, in particular those by Plasmodium species that cause malaria.
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Deppermann C, Kratofil RM, Peiseler M, David BA, Zindel J, Castanheira FVES, van der Wal F, Carestia A, Jenne CN, Marth JD, Kubes P. Macrophage galactose lectin is critical for Kupffer cells to clear aged platelets. J Exp Med 2020; 217:133651. [PMID: 31978220 PMCID: PMC7144524 DOI: 10.1084/jem.20190723] [Citation(s) in RCA: 88] [Impact Index Per Article: 17.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2019] [Revised: 10/01/2019] [Accepted: 12/17/2019] [Indexed: 12/21/2022] Open
Abstract
Every day, megakaryocytes produce billions of platelets that circulate for several days and eventually are cleared by the liver. The exact removal mechanism, however, remains unclear. Loss of sialic acid residues is thought to feature in the aging and clearance of platelets. Using state-of-the-art spinning disk intravital microscopy to delineate the different compartments and cells of the mouse liver, we observed rapid accumulation of desialylated platelets predominantly on Kupffer cells, with only a few on endothelial cells and none on hepatocytes. Kupffer cell depletion prevented the removal of aged platelets from circulation. Ashwell-Morell receptor (AMR) deficiency alone had little effect on platelet uptake. Macrophage galactose lectin (MGL) together with AMR mediated clearance of desialylated or cold-stored platelets by Kupffer cells. Effective clearance is critical, as mice with an aged platelet population displayed a bleeding phenotype. Our data provide evidence that the MGL of Kupffer cells plays a significant role in the removal of desialylated platelets through a collaboration with the AMR, thereby maintaining a healthy and functional platelet compartment.
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Affiliation(s)
- Carsten Deppermann
- Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada.,Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada.,Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Rachel M Kratofil
- Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada.,Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
| | - Moritz Peiseler
- Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada.,Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
| | - Bruna A David
- Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada.,Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
| | - Joel Zindel
- Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada.,Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
| | - Fernanda Vargas E Silva Castanheira
- Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada.,Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
| | - Fardau van der Wal
- Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada.,Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
| | - Agostina Carestia
- Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada.,Department of Microbiology, Immunology and Infectious Diseases, University of Calgary, Calgary, Alberta, Canada
| | - Craig N Jenne
- Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada.,Department of Microbiology, Immunology and Infectious Diseases, University of Calgary, Calgary, Alberta, Canada
| | - Jamey D Marth
- Center for Nanomedicine, SBP Medical Discovery Institute, and Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA
| | - Paul Kubes
- Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada.,Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
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Li L, Zeng Z. Live Imaging of Innate and Adaptive Immune Responses in the Liver. Front Immunol 2020; 11:564768. [PMID: 33042143 PMCID: PMC7527534 DOI: 10.3389/fimmu.2020.564768] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Accepted: 08/13/2020] [Indexed: 12/21/2022] Open
Abstract
Immune response in the liver is determined by the spatial organization and cellular dynamics of hepatic immune cells. The liver vasculature accommodates abundant tissue-resident innate immune cells, such as Kupffer cells, natural killer cells, and natural killer T cells, to ensure efficient intravascular immunosurveillance. The fenestrated sinusoids also allow direct contact between circulating T cells and non-canonical antigen-presenting cells, such as hepatocytes, to instruct adaptive immune responses. Distinct cellular behaviors are exploited by liver immune cells to exert proper functions. Intravital imaging enables real-time visualization of individual immune cell in living animals, representing a powerful tool in dissecting the spatiotemporal features of intrahepatic immune cells during steady state and liver diseases. This review summarizes current advances in liver immunology prompted by in vivo imaging, with a particular focus on liver-resident innate immune cells and hepatic T cells.
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Affiliation(s)
- Lu Li
- The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.,Hefei National Laboratory for Physical Sciences at Microscale, The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Zhutian Zeng
- The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.,Hefei National Laboratory for Physical Sciences at Microscale, The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
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Lercher A, Popa AM, Viczenczova C, Kosack L, Klavins K, Agerer B, Opitz CA, Lanz TV, Platten M, Bergthaler A. Hepatocyte-intrinsic type I interferon signaling reprograms metabolism and reveals a novel compensatory mechanism of the tryptophan-kynurenine pathway in viral hepatitis. PLoS Pathog 2020; 16:e1008973. [PMID: 33045014 PMCID: PMC7580883 DOI: 10.1371/journal.ppat.1008973] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Revised: 10/22/2020] [Accepted: 09/10/2020] [Indexed: 12/27/2022] Open
Abstract
The liver is a central regulator of metabolic homeostasis and serum metabolite levels. Hepatocytes are the functional units of the liver parenchyma and not only responsible for turnover of biomolecules but also act as central immune signaling platforms. Hepatotropic viruses infect liver tissue, resulting in inflammatory responses, tissue damage and hepatitis. Combining well-established in vitro and in vivo model systems with transcriptomic analyses, we show that type I interferon signaling initiates a robust antiviral immune response in hepatocytes. Strikingly, we also identify IFN-I as both, sufficient and necessary, to induce wide-spread metabolic reprogramming in hepatocytes. IFN-I specifically rewired tryptophan metabolism and induced hepatic tryptophan oxidation to kynurenine via Tdo2, correlating with altered concentrations of serum metabolites upon viral infection. Infected Tdo2-deficient animals displayed elevated serum levels of tryptophan and, unexpectedly, also vast increases in the downstream immune-suppressive metabolite kynurenine. Thus, Tdo2-deficiency did not result in altered serum homeostasis of the tryptophan to kynurenine ratio during infection, which seemed to be independent of hepatocyte-intrinsic compensation via the IDO-axis. These data highlight that inflammation-induced reprogramming of systemic tryptophan metabolism is tightly regulated in viral hepatitis. Viral hepatitis is responsible for more than one million annual deaths worldwide and may progress to liver cirrhosis and hepatocellular carcinoma. The main metabolic cell type of the liver is the hepatocyte. In viral hepatitis, type I interferon (IFN-I) signaling rewires hepatocyte metabolism and serum metabolites to shape disease pathophysiology – an immune-regulatory circuit that might be therapeutically exploited. Here, we show that hepatocyte-intrinsic antiviral IFN-I signaling is both necessary and sufficient to induce wide-spread metabolic changes in hepatocytes. We identify a IFN-I-mediated induction of the hepatic kynurenine pathway via the rate-limiting and liver-specific enzyme TDO2, which controls serum homeostasis of tryptophan by converting it into kynurenine. Loss of TDO2 triggers a so far unknown compensatory mechanism, resulting in a vast increase of circulating kynurenine independent of hepatocyte intrinsic activity of the related IDO-enzymes. This study provides new insights into how inflammation reprograms metabolism of the liver and the kynurenine pathway during viral hepatitis.
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MESH Headings
- Animals
- Antiviral Agents/metabolism
- Female
- Hepatitis Viruses/isolation & purification
- Hepatitis, Viral, Animal/immunology
- Hepatitis, Viral, Animal/metabolism
- Hepatitis, Viral, Animal/virology
- Hepatocytes/immunology
- Hepatocytes/metabolism
- Hepatocytes/virology
- Humans
- Immunity, Innate/immunology
- Inflammation/immunology
- Inflammation/metabolism
- Inflammation/pathology
- Inflammation/virology
- Interferon Regulatory Factor-7/physiology
- Kynurenine/metabolism
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Receptor, Interferon alpha-beta/physiology
- STAT1 Transcription Factor/physiology
- Tryptophan/metabolism
- Tryptophan Oxygenase/physiology
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Affiliation(s)
- Alexander Lercher
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse, Vienna, Austria
- * E-mail: (AL); (AB)
| | - Alexandra M. Popa
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse, Vienna, Austria
| | - Csilla Viczenczova
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse, Vienna, Austria
| | - Lindsay Kosack
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse, Vienna, Austria
| | - Kristaps Klavins
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse, Vienna, Austria
| | - Benedikt Agerer
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse, Vienna, Austria
| | - Christiane A. Opitz
- DKTK Brain Cancer Metabolism Group, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Neurology Clinic and National Center for Tumor Diseases, University Hospital of Heidelberg, Heidelberg, Germany
| | - Tobias V. Lanz
- Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, United States of America
- Department of Neurology, University of Heidelberg, Medical Faculty Mannheim, Mannheim, Germany
| | - Michael Platten
- Department of Neurology, University of Heidelberg, Medical Faculty Mannheim, Mannheim, Germany
- DKTK Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Andreas Bergthaler
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse, Vienna, Austria
- * E-mail: (AL); (AB)
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McCaughan GW, Bowen DG, Bertolino PJ. Induction Phase of Spontaneous Liver Transplant Tolerance. Front Immunol 2020; 11:1908. [PMID: 33013840 PMCID: PMC7516030 DOI: 10.3389/fimmu.2020.01908] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Accepted: 07/16/2020] [Indexed: 12/30/2022] Open
Abstract
The liver has long been known to possess tolerogenic properties. Early experiments in liver transplantation demonstrated that in animal models, hepatic allografts could be accepted across MHC-mismatch without the use of immunosuppression, and that transplantation of livers from the same donor was capable of inducing tolerance to other solid organs that would normally otherwise be rejected. Although this phenomenon is less pronounced in human liver transplantation, lower levels of immunosuppression are nevertheless required for graft acceptance than for other solid organs, and in a minority of individuals immunosuppression can be discontinued in the longer term. The mechanisms underlying this unique hepatic property have not yet been fully delineated, however it is clear that immunological events in the early period post-liver transplant are key to generation of hepatic allograft tolerance. Both the hepatic parenchyma and the large number of donor passenger leukocytes contained within the liver allograft have been demonstrated to contribute to the generation of donor-specific tolerance in the early post-transplant phase. In particular, the unique nature of hepatic-leukocyte interactions appears to play a crucial role in the ability of the liver to silence the recipient alloimmune response. In this review, we will summarize the evidence regarding the potential mechanisms that mediate the critical early phase in the generation of hepatic allograft tolerance.
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Affiliation(s)
- Geoffrey W McCaughan
- Liver Injury and Cancer Program, The Centenary Institute, University of Sydney and Royal Prince Alfred Hospital, Sydney, NSW, Australia.,AW Morrow Gastroenterology and Liver Centre, University of Sydney and Royal Prince Alfred Hospital, Sydney, NSW, Australia
| | - David G Bowen
- AW Morrow Gastroenterology and Liver Centre, University of Sydney and Royal Prince Alfred Hospital, Sydney, NSW, Australia.,Liver Immunology Program, The Centenary Institute, University of Sydney and Royal Prince Alfred Hospital, Sydney, NSW, Australia
| | - Patrick J Bertolino
- AW Morrow Gastroenterology and Liver Centre, University of Sydney and Royal Prince Alfred Hospital, Sydney, NSW, Australia.,Liver Immunology Program, The Centenary Institute, University of Sydney and Royal Prince Alfred Hospital, Sydney, NSW, Australia
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Ficht X, Iannacone M. Immune surveillance of the liver by T cells. Sci Immunol 2020; 5:5/51/eaba2351. [PMID: 32887842 DOI: 10.1126/sciimmunol.aba2351] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Accepted: 08/13/2020] [Indexed: 12/14/2022]
Abstract
The liver is the target of several infectious, inflammatory, and neoplastic diseases, which affect hundreds of millions of people worldwide and cause an estimated death toll of more than 2 million people each year. Dysregulation of T cell responses has been implicated in the pathogenesis of these diseases; hence, it is critically important to understand the function and fate of T cells in the liver. Here, we provide an overview of the current knowledge on liver immune surveillance by conventional and invariant T cells and explore the complex cross-talk between immune cell subsets that determines the balance between hepatic immunity and tolerance.
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Affiliation(s)
- Xenia Ficht
- Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.,Vita-Salute San Raffaele University, 20132 Milan, Italy
| | - Matteo Iannacone
- Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy. .,Vita-Salute San Raffaele University, 20132 Milan, Italy.,Experimental Imaging Center, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
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Wilkinson AL, Qurashi M, Shetty S. The Role of Sinusoidal Endothelial Cells in the Axis of Inflammation and Cancer Within the Liver. Front Physiol 2020; 11:990. [PMID: 32982772 PMCID: PMC7485256 DOI: 10.3389/fphys.2020.00990] [Citation(s) in RCA: 79] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Accepted: 07/20/2020] [Indexed: 12/12/2022] Open
Abstract
Liver sinusoidal endothelial cells (LSEC) form a unique barrier between the liver sinusoids and the underlying parenchyma, and thus play a crucial role in maintaining metabolic and immune homeostasis, as well as actively contributing to disease pathophysiology. Whilst their endocytic and scavenging function is integral for nutrient exchange and clearance of waste products, their capillarisation and dysfunction precedes fibrogenesis. Furthermore, their ability to promote immune tolerance and recruit distinct immunosuppressive leukocyte subsets can allow persistence of chronic viral infections and facilitate tumour development. In this review, we present the immunological and barrier functions of LSEC, along with their role in orchestrating fibrotic processes which precede tumourigenesis. We also summarise the role of LSEC in modulating the tumour microenvironment, and promoting development of a pre-metastatic niche, which can drive formation of secondary liver tumours. Finally, we summarise closely inter-linked disease pathways which collectively perpetuate pathogenesis, highlighting LSEC as novel targets for therapeutic intervention.
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Affiliation(s)
| | | | - Shishir Shetty
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
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Tsomaia K, Patarashvili L, Karumidze N, Bebiashvili I, Azmaipharashvili E, Modebadze I, Dzidziguri D, Sareli M, Gusev S, Kordzaia D. Liver structural transformation after partial hepatectomy and repeated partial hepatectomy in rats: A renewed view on liver regeneration. World J Gastroenterol 2020; 26:3899-3916. [PMID: 32774065 PMCID: PMC7385567 DOI: 10.3748/wjg.v26.i27.3899] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Revised: 05/12/2020] [Accepted: 06/23/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The phenomenon of liver regeneration after partial hepatectomy (PH) is still a subject of considerable interest due to the increasing frequency of half liver transplantation on the one hand, and on the other hand, new surgical approaches which allow removal of massive space-occupying hepatic tumors, which earlier was considered as inoperable. Interestingly, the mechanisms of liver regeneration are extensively studied after PH but less attention is paid to the architectonics of the regenerated organ. Because of this, the question "How does the structure of regenerated liver differ from normal, regular liver?" has not been fully answered yet. Furthermore, almost without any attention is left the liver's structural transformation after repeated hepatectomy (of the re-regenereted liver). AIM To compare the architectonics of the lobules and circulatory bed of normal, re-generated and re-regenerated livers. METHODS The livers of 40 adult, male, albino Wistar rats were studied. 14 rats were subjected to PH - the 1st study group (SG1); 10 rats underwent repeated PH - the 2nd study group (SG2); 16 rats were subjected to sham operation - control group (CG); The livers were studied after 9 months from PH, and after 6 months from repeated PH. Cytological (Schiff reaction for the determination of DNA concen-tration), histological (H&E, Masson trichrome, CK8 Immunohistochemical marker, transparent slides after Indian Ink injection, ), morphometrical (hepatocytes areas, perimeters and ploidy) and Electron Microscopical (Scanning Electron Microscopy of corrosion casts) methods were used. RESULTS In the SG1 and SG2, the area of hepatocytes and their perimeter are increased compared to the CG (P < 0.05). However, the areas and perimeters of the hepatocytes of the SG1 and SG2 groups reveal a lesser difference. In regenerated (SG1) and re-regenerated (SG2) livers, the hepatocytes form the remodeled lobules, which size (300-1200 µm) exceeds the sizes of the lobules from CG (300-600 µm). The remodeled lobules (especially the "mega-lobules" with the sizes 1000-1200 µm) contain the transformed meshworks of the sinusoids, the part of which is dilated asymmetrically. This meshwork might have originated from the several portal venules (interlobular and/or inlet). The boundaries between the adjacent lobules (including mega-lobules) are widened and filled by connective tissue fibers, which gives the liver parenchyma a nodular look. In SG2 the unevenness of sinusoid diameters, as well as the boundaries between the lobules (including the mega-lobules) are more vividly expressed in comparison with SG1. The liver tissue of both SG1 and SG2 is featured by the slightly expressed ductular reaction. CONCLUSION Regenerated and re-regenerated livers in comparison with normal liver contain hypertrophied hepatocytes with increased ploidy which together with transformed sinusoidal and biliary meshworks form the remodeled lobulli.
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Affiliation(s)
- Keti Tsomaia
- Faculty of Medicine, Ivane Javakhishvili Tbilisi State University, Tbilisi 0159, Georgia
| | - Leila Patarashvili
- Faculty of Medicine, Ivane Javakhishvili Tbilisi State University, Tbilisi 0159, Georgia
| | - Nino Karumidze
- Faculty of Medicine, Ivane Javakhishvili Tbilisi State University, Tbilisi 0159, Georgia
| | - Irakli Bebiashvili
- Faculty of Medicine, Ivane Javakhishvili Tbilisi State University, Tbilisi 0159, Georgia
| | - Elza Azmaipharashvili
- Faculty of Medicine, Ivane Javakhishvili Tbilisi State University, Tbilisi 0159, Georgia
| | - Irina Modebadze
- Faculty of Exact and Natural Sciences, Ivane Javakhishvili Tbilisi State University, Tbilisi 0179, Georgia
| | - Diana Dzidziguri
- Faculty of Exact and Natural Sciences, Ivane Javakhishvili Tbilisi State University, Tbilisi 0179, Georgia
| | - Marom Sareli
- Department of Surgical Oncology (Surgery C), Chaim Sheba Medical Center at HaShomer, Tel Aviv 52621, Israel
| | - Sergey Gusev
- Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow 119435, Russia
| | - Dimitri Kordzaia
- Faculty of Medicine, Ivane Javakhishvili Tbilisi State University, Tbilisi 0159, Georgia
- Clinical Anatomy and Operative Surgery, Ivane Javakhishvili Tbilisi State University, Tbilisi 0159, Georgia
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49
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Jiang Y, Que W, Zhu P, Li XK. The Role of Diverse Liver Cells in Liver Transplantation Tolerance. Front Immunol 2020; 11:1203. [PMID: 32595648 PMCID: PMC7304488 DOI: 10.3389/fimmu.2020.01203] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2020] [Accepted: 05/14/2020] [Indexed: 12/11/2022] Open
Abstract
Liver transplantation is the ideal treatment approach for a variety of end-stage liver diseases. However, life-long, systemic immunosuppressive treatment after transplantation is required to prevent rejection and graft loss, which is associated with severe side effects, although liver allograft is considered more tolerogenic. Therefore, understanding the mechanism underlying the unique immunologically privileged liver organ is valuable for transplantation management and autoimmune disease treatment. The unique hepatic acinus anatomy and a complex cellular network constitute the immunosuppressive hepatic microenvironment, which are responsible for the tolerogenic properties of the liver. The hepatic microenvironment contains a variety of hepatic-resident immobile non-professional antigen-presenting cells, including hepatocytes, liver sinusoidal endothelial cells, Kupffer cells, and hepatic stellate cells, that are insufficient to optimally prime T cells locally and lead to the removal of alloreactive T cells due to the low expression of major histocompatibility complex (MHC) molecules, costimulatory molecules and proinflammatory cytokines but a rather high expression of coinhibitory molecules and anti-inflammatory cytokines. Hepatic dendritic cells (DCs) are generally immature and less immunogenic than splenic DCs and are also ineffective in priming naïve allogeneic T cells via the direct recognition pathway in recipient secondary lymphoid organs. Although natural killer cells and natural killer T cells are reportedly associated with liver tolerance, their roles in liver transplantation are multifaceted and need to be further clarified. Under these circumstances, T cells are prone to clonal deletion, clonal anergy and exhaustion, eventually leading to tolerance. Other proposed liver tolerance mechanisms, such as soluble donor MHC class I molecules, passenger leukocytes theory and a high-load antigen effect, have also been addressed. We herein comprehensively review the current evidence implicating the tolerogenic properties of diverse liver cells in liver transplantation tolerance.
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Affiliation(s)
- Yanzhi Jiang
- Division of Transplantation Immunology, National Research Institute for Child Health and Development, Tokyo, Japan.,Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Weitao Que
- Division of Transplantation Immunology, National Research Institute for Child Health and Development, Tokyo, Japan
| | - Ping Zhu
- Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Xiao-Kang Li
- Division of Transplantation Immunology, National Research Institute for Child Health and Development, Tokyo, Japan
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50
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Michalak TI. Diverse Virus and Host-Dependent Mechanisms Influence the Systemic and Intrahepatic Immune Responses in the Woodchuck Model of Hepatitis B. Front Immunol 2020; 11:853. [PMID: 32536912 PMCID: PMC7267019 DOI: 10.3389/fimmu.2020.00853] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Accepted: 04/14/2020] [Indexed: 12/15/2022] Open
Abstract
Woodchuck infected with woodchuck hepatitis virus (WHV) represents the pathogenically nearest model of hepatitis B and associated hepatocellular carcinoma (HCC). This naturally occurring animal model also is highly valuable for development and preclinical evaluation of new anti-HBV agents and immunotherapies against chronic hepatitis (CH) B and HCC. Studies in this system uncovered a number of molecular and immunological processes which contribute or likely contribute to the immunopathogenesis of liver disease and modulation of the systemic and intrahepatic innate and adaptive immune responses during hepadnaviral infection. Among them, inhibition of presentation of the class I major histocompatibility complex on chronically infected hepatocytes and a role of WHV envelope proteins in this process, as well as augmented hepatocyte cytotoxicity mediated by constitutively expressed components of CD95 (Fas) ligand- and perforin-dependent pathways, capable of eliminating cells brought to contact with hepatocyte surface, including activated T lymphocytes, were uncovered. Other findings pointed to a role of autoimmune response against hepatocyte asialoglycoprotein receptor in augmenting severity of liver damage in hepadnaviral CH. It was also documented that WHV in the first few hours activates intrahepatic innate immunity that transiently decreases hepatic virus load. However, this activation is not translated in a timely manner to induction of virus-specific T cell response which appears to be hindered by defective activation of antigen presenting cells and presentation of viral epitopes to T cells. The early WHV infection also induces generalized polyclonal activation of T cells that precedes emergence of virus-specific T lymphocyte reactivity. The combination of these mechanisms hinder recognition of virus allowing its dissemination in the initial, asymptomatic stages of infection before adaptive cellular response became apparent. This review will highlight a range of diverse mechanisms uncovered in the woodchuck model which affect effectiveness of the anti-viral systemic and intrahepatic immune responses, and modify liver disease outcomes. Further exploration of these and other mechanisms, either already discovered or yet unknown, and their interactions should bring more comprehensive understanding of HBV pathogenesis and help to identify novel targets for therapeutic and preventive interventions. The woodchuck model is uniquely positioned to further contribute to these advances.
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Affiliation(s)
- Tomasz I Michalak
- Molecular Virology and Hepatology Research Group, Division of BioMedical Sciences, Faculty of Medicine, Health Sciences Centre, Memorial University of Newfoundland, St. John's, NL, Canada
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