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1
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Yang L, Zheng SG. Role of regulatory T cells in inflammatory liver diseases. Autoimmun Rev 2025; 24:103806. [PMID: 40139456 DOI: 10.1016/j.autrev.2025.103806] [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: 07/08/2024] [Revised: 03/21/2025] [Accepted: 03/21/2025] [Indexed: 03/29/2025]
Abstract
The liver is the human body's largest digestive gland, which can participate in digestion, metabolism, excretion, detoxification and immunity. Chronic liver diseases such as metabolic dysfunction-associated fatty liver disease (MAFLD) or viral hepatitis involve ongoing inflammation and resulting liver fibrosis may ultimately lead to the development of hepatobiliary cancers (HCC). Inflammation is the coordinated reaction of different liver cell types to cell signals and death of inflammation, which are linked to injury pathways within the liver or external agents from the gut-liver axis and the circulation. Regulatory T (Treg) cells play a crucial role in controlling inflammation and are essential for maintaining immune tolerance and balance. In this review, we highlight the recent discoveries related to the function of immune systems in liver inflammation and discuss the role of Treg cells in the different liver diseases (including MAFLD, autoimmune hepatitis and others).
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Affiliation(s)
- Linjie Yang
- The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan 523808, China
| | - Song Guo Zheng
- The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan 523808, China; Department of Immunology, School of Cell and Gene Therapy, Songjiang Research Institute, Shanghai Songjiang District Central Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201600, China; State Key Laboratory of Innovative Immunotherapy, Shanghai Jiao Tong University, Shanghai, 201600, China.
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2
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Schwabe RF, Brenner DA. Hepatic stellate cells: balancing homeostasis, hepatoprotection and fibrogenesis in health and disease. Nat Rev Gastroenterol Hepatol 2025:10.1038/s41575-025-01068-6. [PMID: 40404839 DOI: 10.1038/s41575-025-01068-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/03/2025] [Indexed: 05/24/2025]
Abstract
In the past decades, the pathogenic role of hepatic stellate cells (HSCs) in the development of liver fibrosis and its complications has been deeply characterized, rendering HSCs a primary target for antifibrotic therapies. By contrast, the beneficial roles of HSCs in liver homeostasis and liver disease are only beginning to emerge, revealing critical regulatory and fibrosis-independent functions in hepatic zonation, metabolism, injury, regeneration and non-parenchymal cell identity. Here, we review how HSC mediators, such as R-spondin 3, hepatocyte growth factor and bone morphogenetic proteins, regulate critical and homeostatic liver functions in health and disease via cognate receptors in hepatocytes, Kupffer cells and endothelial cells. We highlight how the balance shifts from protective towards fibropathogenic HSC mediators during the progression of chronic liver disease (CLD) and the impact of this shifted balance on patient outcomes. Notably, the protective roles of HSCs are not accounted for in current therapeutic concepts for CLD. We discuss the concept that reverting the HSC balance from fibrogenesis towards hepatoprotection might represent a novel holistic treatment approach to inhibit fibrogenesis and restore epithelial health in CLD simultaneously.
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Affiliation(s)
- Robert F Schwabe
- Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, New York, NY, USA.
- Columbia University Digestive and Liver Disease Research Center, New York, NY, USA.
- Herbert Irving Comprehensive Cancer Center, New York, NY, USA.
- Institute of Human Nutrition, New York, NY, USA.
| | - David A Brenner
- Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA
- Division of Gastroenterology and Hepatology, Department of Medicine, UC San Diego, La Jolla, CA, USA
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3
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Castanho Martins M, Dixon ED, Lupo G, Claudel T, Trauner M, Rombouts K. Role of PNPLA3 in Hepatic Stellate Cells and Hepatic Cellular Crosstalk. Liver Int 2025; 45:e16117. [PMID: 39394864 PMCID: PMC11891384 DOI: 10.1111/liv.16117] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Revised: 09/16/2024] [Accepted: 09/17/2024] [Indexed: 10/14/2024]
Abstract
AIMS Since its discovery, the patatin-like phospholipase domain containing 3 (PNPLA3) (rs738409 C>G p.I148M) variant has been studied extensively to unravel its molecular function. Although several studies proved a causal relationship between the PNPLA3 I148M variant and MASLD development and particularly fibrosis, the pathological mechanisms promoting this phenotype have not yet been fully clarified. METHODS We summarise the latest data regarding the PNPLA3 I148M variant in hepatic stellate cells (HSCs) activation and macrophage biology or the path to inflammation-induced fibrosis. RESULTS Elegant but contradictory studies have ascribed PNPLA3 a hydrolase or an acyltransferase function. The PNPLA3 I148M results in hepatic lipid accumulation, which predisposes the hepatocyte to lipotoxicity and lipo-apoptosis, producing DAMPs, cytokines and chemokines leading to recruitment and activation of macrophages and HSCs, propagating fibrosis. Recent studies showed that the PNPLA3 I148M variant alters HSCs biology via attenuation of PPARγ, AP-1, LXRα and TGFβ activity and signalling. CONCLUSIONS The advent of refined techniques in isolating HSCs has made PNPLA3's direct role in HSCs for liver fibrosis development more apparent. However, many other mechanisms still need detailed investigations.
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Affiliation(s)
- Maria Castanho Martins
- Regenerative Medicine and Fibrosis Group, Institute for Liver and Digestive HealthUniversity College London, Royal Free CampusLondonUK
| | - Emmanuel Dauda Dixon
- Hans Popper Laboratory of Molecular Hepatology, Department of Internal Medicine IIIMedical University of ViennaViennaAustria
| | - Giulia Lupo
- Regenerative Medicine and Fibrosis Group, Institute for Liver and Digestive HealthUniversity College London, Royal Free CampusLondonUK
| | - Thierry Claudel
- Hans Popper Laboratory of Molecular Hepatology, Department of Internal Medicine IIIMedical University of ViennaViennaAustria
| | - Michael Trauner
- Hans Popper Laboratory of Molecular Hepatology, Department of Internal Medicine IIIMedical University of ViennaViennaAustria
| | - Krista Rombouts
- Regenerative Medicine and Fibrosis Group, Institute for Liver and Digestive HealthUniversity College London, Royal Free CampusLondonUK
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4
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Zheng H, Xu B, Fan Y, Tuekprakhon A, Stamataki Z, Wang F. The role of immune regulation in HBV infection and hepatocellular carcinogenesis. Front Immunol 2025; 16:1506526. [PMID: 40160817 PMCID: PMC11949809 DOI: 10.3389/fimmu.2025.1506526] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2024] [Accepted: 02/19/2025] [Indexed: 04/02/2025] Open
Abstract
Hepatitis B virus (HBV) infection is a well-documented independent risk factor for developing hepatocellular carcinoma (HCC). Consequently, extensive research has focused on elucidating the mechanisms by which HBV induces hepatocarcinogenesis. The majority of studies are dedicated to understanding how HBV DNA integration into the host genome, viral RNA expression, and the resulting protein transcripts affect cellular processes and promote the malignant transformation of hepatocytes. However, considering that most acute HBV infections are curable, immune suppression potentially contributes to the critical challenges in the treatment of chronic infections. Regulatory T cells (Tregs) are crucial in immune tolerance. Understanding the interplay of Tregs within the liver microenvironment following HBV infection could offer novel therapeutic approaches for treating HBV infections and preventing HBV-related HCC. Two viewpoints to targeting Tregs in the liver microenvironment include means of reducing their inhibitory function and decreasing Treg frequency. As these strategies may disrupt the immune balance and lead to autoimmune responses, careful and comprehensive profiling of the patient's immunological status and genetic factors is required to successfully employ this promising therapeutic approach.
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Affiliation(s)
- Hailong Zheng
- Department of Hepatobiliary, Pancreatic, and Spleen Surgery, Affiliated Hospital of Inner Mongolia Medical University, Inner Mongolia Medical University, Hohhot, Inner Mongolia Autonomous Region, China
| | - Bingchen Xu
- Department of Hepatobiliary, Pancreatic, and Spleen Surgery, Affiliated Hospital of Inner Mongolia Medical University, Inner Mongolia Medical University, Hohhot, Inner Mongolia Autonomous Region, China
| | - Yiyu Fan
- Centre for Liver and Gastrointestinal Research, School of Infection, Inflammation & Immunology, College of Medicine and Health, University of Birmingham, Birmingham, United Kingdom
| | - Aekkachai Tuekprakhon
- Department of Hepatobiliary, Pancreatic, and Spleen Surgery, Affiliated Hospital of Inner Mongolia Medical University, Inner Mongolia Medical University, Hohhot, Inner Mongolia Autonomous Region, China
- Centre for Liver and Gastrointestinal Research, School of Infection, Inflammation & Immunology, College of Medicine and Health, University of Birmingham, Birmingham, United Kingdom
| | - Zania Stamataki
- Centre for Liver and Gastrointestinal Research, School of Infection, Inflammation & Immunology, College of Medicine and Health, University of Birmingham, Birmingham, United Kingdom
| | - Fei Wang
- Department of Hepatobiliary, Pancreatic, and Spleen Surgery, Affiliated Hospital of Inner Mongolia Medical University, Inner Mongolia Medical University, Hohhot, Inner Mongolia Autonomous Region, China
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5
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Jones PC, Von Hoff DD. Vitamin A Metabolism and Resistance of Hepatic Metastases to Immunotherapy. Mol Cancer Ther 2025; 24:345-353. [PMID: 39363636 PMCID: PMC11876961 DOI: 10.1158/1535-7163.mct-24-0367] [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: 05/23/2024] [Revised: 08/05/2024] [Accepted: 09/27/2024] [Indexed: 10/05/2024]
Abstract
The liver is an immune-tolerant organ, allowing for organ transplantation with less immune suppression compared with other organs. It also provides fertile soil for tumor metastases, which tend to be more resistant to checkpoint blockade immunotherapy than metastases in other organs. This resistance may result from the sum of incremental evolutionary adaptions in various cell types to prevent overaction to antigens absorbed from the gut into the portal circulation or it might involve a central mechanism. Here, we propose that metabolism of vitamin A, which is highly concentrated in the liver, is a root source of tolerance and resistance of hepatic metastases to checkpoint blockade. Suppression of retinoic acid synthesis from vitamin A with disulfiram may mitigate tolerance and produce enhanced immunotherapy treatment results for patients with liver metastases.
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Affiliation(s)
| | - Daniel D. Von Hoff
- HonorHealth Research Institute (HHRI), Scottsdale, Arizona
- Translational Genomics Research Institute (TGen) a Part of City of Hope, Phoenix, Arizona
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6
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Xu X, Liu J, Li X, Feng Q, Su Y. Integrated network pharmacology and metabolomics to study the potential mechanism of Jiawei Yinchenhao decoction in chronic hepatitis B. Heliyon 2024; 10:e36267. [PMID: 39224343 PMCID: PMC11367511 DOI: 10.1016/j.heliyon.2024.e36267] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2024] [Revised: 08/01/2024] [Accepted: 08/13/2024] [Indexed: 09/04/2024] Open
Abstract
Chronic hepatitis B infection (CHB) is a major risk factor for the development of hepatocellular carcinoma (HCC) globally and continues to pose a significant global health challenge. Jiawei Yinchenhao decoction (JWYCH) is a modified version of Yinchenhao decoction (YCHD), which is widely used to treat liver diseases including icteric hepatitis, cholelithiasis, and hepatic ascites. However, the effectiveness and underlying mechanism of JWYCH on CHB are still unclear. This study aimed to investigate the impact of JWYCH on CHB and explore the underlying mechanism via network pharmacology and metabolomics. C57BL/6 mice were administered rAAV-HBV1.3 via hydrodynamic injection (HDI) to establish the CHB model. The infected mice were orally administered JWYCH for 4 weeks. HBsAg, HBeAg, HBV DNA, the serum liver function index, and histopathology were detected. In addition, network pharmacology was used to investigate potential targets, whereas untargeted metabolomics analysis was employed to explore the hepatic metabolic changes in JWYCH in CHB mice and identify relevant biomarkers and metabolic pathways. JWYCH was able to reduce HBeAg levels and improve liver pathological changes in mice with CHB. Additionally, metabolomics analysis indicated that JWYCH can influence 105 metabolites, including pipecolic acid, alpha-terpinene, adenosine, and L-phenylalanine, among others. Bile acid metabolism, arachidonic acid metabolism, and retinol metabolism are suggested to be potential targets of JWYCH in CHB. In conclusion, JWYCH demonstrated a hepatoprotective effect on a mouse model of CHB, suggesting a potential alternative therapeutic strategy for CHB. The effect of JWYCH is associated mainly with regulating the metabolism of bile acid, arachidonic acid, and retinol. These differentially abundant metabolites may serve as potential biomarkers and therapeutic targets for CHB.
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Affiliation(s)
- Xinyi Xu
- College of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Jin Liu
- College of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Xue Li
- College of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - QuanSheng Feng
- College of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Yue Su
- College of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
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7
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Abdelnabi MN, Hassan GS, Shoukry NH. Role of the type 3 cytokines IL-17 and IL-22 in modulating metabolic dysfunction-associated steatotic liver disease. Front Immunol 2024; 15:1437046. [PMID: 39156888 PMCID: PMC11327067 DOI: 10.3389/fimmu.2024.1437046] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2024] [Accepted: 07/12/2024] [Indexed: 08/20/2024] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) comprises a spectrum of liver diseases that span simple steatosis, metabolic dysfunction-associated steatohepatitis (MASH) and fibrosis and may progress to cirrhosis and cancer. The pathogenesis of MASLD is multifactorial and is driven by environmental, genetic, metabolic and immune factors. This review will focus on the role of the type 3 cytokines IL-17 and IL-22 in MASLD pathogenesis and progression. IL-17 and IL-22 are produced by similar adaptive and innate immune cells such as Th17 and innate lymphoid cells, respectively. IL-17-related signaling is upregulated during MASLD resulting in increased chemokines and proinflammatory cytokines in the liver microenvironment, enhanced recruitment of myeloid cells and T cells leading to exacerbation of inflammation and liver disease progression. IL-17 may also act directly by activating hepatic stellate cells resulting in increased fibrosis. In contrast, IL-22 is a pleiotropic cytokine with a dominantly protective signature in MASLD and is currently being tested as a therapeutic strategy. IL-22 also exhibits beneficial metabolic effects and abrogates MASH-related inflammation and fibrosis development via inducing the production of anti-oxidants and anti-apoptotic factors. A sex-dependent effect has been attributed to both cytokines, most importantly to IL-22 in MASLD or related conditions. Altogether, IL-17 and IL-22 are key effectors in MASLD pathogenesis and progression. We will review the role of these two cytokines and cells that produce them in the development of MASLD, their interaction with host factors driving MASLD including sexual dimorphism, and their potential therapeutic benefits.
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Affiliation(s)
- Mohamed N. Abdelnabi
- Centre de Recherche du Centre hospitalier de l’Université de Montréal (CRCHUM), Montréal, QC, Canada
- Département de microbiologie, infectiologie et immunologie, Faculté de médecine, Université de Montréal, Montréal, QC, Canada
| | - Ghada S. Hassan
- Centre de Recherche du Centre hospitalier de l’Université de Montréal (CRCHUM), Montréal, QC, Canada
| | - Naglaa H. Shoukry
- Centre de Recherche du Centre hospitalier de l’Université de Montréal (CRCHUM), Montréal, QC, Canada
- Département de médecine, Faculté de médecine, Université de Montréal, Montréal, QC, Canada
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8
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Liam-Or R, Faruqu FN, Walters A, Han S, Xu L, Wang JTW, Oberlaender J, Sanchez-Fueyo A, Lombardi G, Dazzi F, Mailaender V, Al-Jamal KT. Cellular uptake and in vivo distribution of mesenchymal-stem-cell-derived extracellular vesicles are protein corona dependent. NATURE NANOTECHNOLOGY 2024; 19:846-855. [PMID: 38366223 PMCID: PMC11186763 DOI: 10.1038/s41565-023-01585-y] [Citation(s) in RCA: 45] [Impact Index Per Article: 45.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Accepted: 11/27/2023] [Indexed: 02/18/2024]
Abstract
Extracellular vesicles (EVs) derived from mesenchymal stem cells are promising nanotherapeutics in liver diseases due to their regenerative and immunomodulatory properties. Nevertheless, a concern has been raised regarding the rapid clearance of exogenous EVs by phagocytic cells. Here we explore the impact of protein corona on EVs derived from two culturing conditions in which specific proteins acquired from media were simultaneously adsorbed on the EV surface. Additionally, by incubating EVs with serum, simulating protein corona formation upon systemic delivery, further resolved protein corona-EV complex patterns were investigated. Our findings reveal the potential influences of corona composition on EVs under in vitro conditions and their in vivo kinetics. Our data suggest that bound albumin creates an EV signature that can retarget EVs from hepatic macrophages. This results in markedly improved cellular uptake by hepatocytes, liver sinusoidal endothelial cells and hepatic stellate cells. This phenomenon can be applied as a camouflage strategy by precoating EVs with albumin to fabricate the albumin-enriched protein corona-EV complex, enhancing non-phagocytic uptake in the liver. This work addresses a critical challenge facing intravenously administered EVs for liver therapy by tailoring the protein corona-EV complex for liver cell targeting and immune evasion.
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Affiliation(s)
- Revadee Liam-Or
- Institute of Pharmaceutical Science, Faculty of Life Sciences & Medicine, King's College London, London, UK
| | - Farid N Faruqu
- Institute of Pharmaceutical Science, Faculty of Life Sciences & Medicine, King's College London, London, UK
- Pharmacology Department, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Adam Walters
- Institute of Pharmaceutical Science, Faculty of Life Sciences & Medicine, King's College London, London, UK
| | - Shunping Han
- Institute of Pharmaceutical Science, Faculty of Life Sciences & Medicine, King's College London, London, UK
| | - Lizhou Xu
- Institute of Pharmaceutical Science, Faculty of Life Sciences & Medicine, King's College London, London, UK
| | - Julie Tzu-Wen Wang
- Institute of Pharmaceutical Science, Faculty of Life Sciences & Medicine, King's College London, London, UK
| | - Jennifer Oberlaender
- Max Planck Institute for Polymer Research, Mainz, Germany
- Department of Dermatology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
| | - Alberto Sanchez-Fueyo
- Institute of Liver Studies, King's College London University and King's College Hospital, London, UK
| | - Giovanna Lombardi
- Peter Gorer Department of Immunobiology, School of Immunology and Microbial Sciences, King's College London, London, UK
| | - Francesco Dazzi
- Comprehensive Cancer Centre, King's College London, London, UK
| | - Volker Mailaender
- Max Planck Institute for Polymer Research, Mainz, Germany
- Department of Dermatology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
| | - Khuloud T Al-Jamal
- Institute of Pharmaceutical Science, Faculty of Life Sciences & Medicine, King's College London, London, UK.
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9
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Kim JW, Kim YJ. The evidence-based multifaceted roles of hepatic stellate cells in liver diseases: A concise review. Life Sci 2024; 344:122547. [PMID: 38460810 DOI: 10.1016/j.lfs.2024.122547] [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: 12/25/2023] [Revised: 02/21/2024] [Accepted: 03/04/2024] [Indexed: 03/11/2024]
Abstract
Hepatic stellate cells (HSCs) play central roles in liver disease pathogenesis, spanning steatosis to cirrhosis and hepatocellular carcinoma. These cells, located in the liver's sinusoidal space of Disse, transition from a quiescent, vitamin A-rich state to an activated, myofibroblast-like phenotype in response to liver injury. This activation results from a complex interplay of cytokines, growth factors, and oxidative stress, leading to excessive collagen deposition and liver fibrosis, a hallmark of chronic liver diseases. Recently, HSCs have gained recognition for their dynamic, multifaceted roles in liver health and disease. Attention has shifted toward their involvement in various liver conditions, including acute liver injury, alcoholic and non-alcoholic fatty liver disease, and liver regeneration. This review aims to explore diverse functions of HSCs in these acute or chronic liver pathologies, with a focus on their roles beyond fibrogenesis. HSCs exhibit a wide range of actions, including lipid storage, immunomodulation, and interactions with other hepatic and extrahepatic cells, making them pivotal in the hepatic microenvironment. Understanding HSC involvement in the progression of liver diseases can offer novel insights into pathogenic mechanisms and guide targeted therapeutic strategies for various liver conditions.
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Affiliation(s)
- Jong-Won Kim
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Yu Ji Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Medical School, Jeonbuk National University, Research Institute of Clinical Medicine of Jeonbuk National University - Biomedical Research Institute of Jeonbuk National University Hospital, Jeonju, South Korea.
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10
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He J, Miao R, Chen Y, Wang H, Liu M. The dual role of regulatory T cells in hepatitis B virus infection and related hepatocellular carcinoma. Immunology 2024; 171:445-463. [PMID: 38093705 DOI: 10.1111/imm.13738] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Accepted: 11/27/2023] [Indexed: 03/09/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is a major contributor to cancer-related deaths worldwide. Hepatitis B virus (HBV) infection is a major etiologic factor leading to HCC. While there have been significant advancements in controlling HBV replication, achieving a complete cure for HBV-related HCC (HBV-HCC) remains an intricate challenge. HBV persistence is attributed to a myriad of mechanisms, encompassing both innate and adaptive immune responses. Regulatory T cells (Tregs) are pivotal in upholding immune tolerance and modulating excessive immune activation. During HBV infection, Tregs mediate specific T cell suppression, thereby contributing to both persistent infection and the mitigation of liver inflammatory responses. Studies have demonstrated an augmented expression of circulating and intrahepatic Tregs in HBV-HCC, which correlates with impaired CD8+ T cell function. Consequently, Tregs play a dual role in the context of HBV infection and the progression of HBV-HCC. In this comprehensive review, we discuss pertinent studies concerning Tregs in HBV infection, HBV-related cirrhosis and HCC. Furthermore, we summarize Treg responses to antiviral therapy and provide Treg-targeted therapies specific to HBV and HCC.
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Affiliation(s)
- Jinan He
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Rui Miao
- Guangzhou Women and Children Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Yao Chen
- Department of Internal Medicine, Northeast Yunnan Regional Central Hospital, Zhaotong, Yunan, China
| | - Han Wang
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Hubei Key Laboratory of Hepato-Biliary-Pancreatic Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Mei Liu
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
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11
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Sun L, Zheng M, Gao Y, Brigstock DR, Gao R. Retinoic acid signaling pathway in pancreatic stellate cells: Insight into the anti-fibrotic effect and mechanism. Eur J Pharmacol 2024; 967:176374. [PMID: 38309676 DOI: 10.1016/j.ejphar.2024.176374] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2023] [Revised: 01/15/2024] [Accepted: 01/30/2024] [Indexed: 02/05/2024]
Abstract
Pancreatic stellate cells (PSCs) are activated following loss of cytoplasmic vitamin A (retinol)-containing lipid droplets, which is a key event in the process of fibrogenesis of chronic pancreatitis (CP) and pancreatic ductal adenocarcinoma (PDCA). PSCs are the major source of cancer-associated fibroblasts (CAFs) that produce stroma to induce PDAC cancer cell growth, invasion, and metastasis. As an active metabolite of retinol, retinoic acid (RA) can regulate target gene expression in PSCs through its nuclear receptor complex (RAR/RXR or RXR/RXR) or transcriptional intermediary factor. Additionally, RA also has extranuclear and non-transcriptional effects. In vitro studies have shown that RA induces PSC deactivation which reduces extracellular matrix production through multiple modes of action, such as inhibiting TβRⅡ, PDGFRβ, β-catenin and Wnt production, downregulating ERK1/2 and JNK phosphorylation and suppressing active TGF-β1 release. RA alone or in combination with other reagents have been demonstrated to have an effective anti-fibrotic effect on cerulein-induced mouse CP models in vivo studies. Clinical trial data have shown that repurposing all-trans retinoic acid (ATRA) as a stromal-targeting agent for human pancreatic cancer is safe and tolerable, suggesting the possibility of using RA for the treatment of CP and PDCA in humans. This review focuses on RA signaling pathways in PSCs and the effects and mechanisms of RA in PSC-mediated fibrogenesis as well as the anti-fibrotic and anti-tumor effects of RA targeting PSCs or CAFs in vitro and in vivo, highlighting the potential therapies of RA against CP and PDAC.
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Affiliation(s)
- Li Sun
- Department of Hepatic Biliary Pancreatic Medicine, First Hospital of Jilin University, Changchun, China; Department of Pathology, First Hospital of Jilin University, Changchun, China
| | - Meifang Zheng
- Department of Hepatic Biliary Pancreatic Medicine, First Hospital of Jilin University, Changchun, China; Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China
| | - Yanhang Gao
- Department of Hepatic Biliary Pancreatic Medicine, First Hospital of Jilin University, Changchun, China; Department of Infectious Diseases, First Hospital of Jilin University, Changchun, China.
| | - David R Brigstock
- The Research Institute at Nationwide Children's Hospital, Columbus, OH, United States
| | - Runping Gao
- Department of Hepatic Biliary Pancreatic Medicine, First Hospital of Jilin University, Changchun, China; Department of Infectious Diseases, First Hospital of Jilin University, Changchun, China.
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12
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Porto E, De Backer J, Thuy LTT, Kawada N, Hankeln T. Transcriptomics of a cytoglobin knockout mouse: Insights from hepatic stellate cells and brain. J Inorg Biochem 2024; 250:112405. [PMID: 37977965 DOI: 10.1016/j.jinorgbio.2023.112405] [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: 06/12/2023] [Revised: 10/10/2023] [Accepted: 10/16/2023] [Indexed: 11/19/2023]
Abstract
The vertebrate respiratory protein cytoglobin (Cygb) is thought to exert multiple cellular functions. Here we studied the phenotypic effects of a Cygb knockout (KO) in mouse on the transcriptome level. RNA sequencing (RNA-Seq) was performed for the first time on sites of major endogenous Cygb expression, i.e. quiescent and activated hepatic stellate cells (HSCs) and two brain regions, hippocampus and hypothalamus. The data recapitulated the up-regulation of Cygb during HSC activation and its expression in the brain. Differential gene expression analyses suggested a role of Cygb in the response to inflammation in HSCs and its involvement in retinoid metabolism, retinoid X receptor (RXR) activation-induced xenobiotics metabolism, and RXR activation-induced lipid metabolism and signaling in activated cells. Unexpectedly, only minor effects of the Cygb KO were detected in the transcriptional profiles in hippocampus and hypothalamus, precluding any enrichment analyses. Furthermore, the transcriptome data pointed at a previously undescribed potential of the Cygb- knockout allele to produce cis-acting effects, necessitating future verification studies.
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Affiliation(s)
- Elena Porto
- Institute of Organismic and Molecular Evolution, Molecular Genetics & Genome Analysis Group, Johannes Gutenberg University Mainz, J. J. Becher-Weg 30A, Mainz D-55128, Germany
| | - Joey De Backer
- Research Group PPES, Department of Biomedical Sciences, University of Antwerp, Universiteitsplein 1, Wilrijk, Antwerp 1610, Belgium
| | - Le Thi Thanh Thuy
- Department of Hepatology, Graduate School of Medicine, Osaka Metropolitan University, Osaka 545-8585, Japan
| | - Norifumi Kawada
- Department of Hepatology, Graduate School of Medicine, Osaka Metropolitan University, Osaka 545-8585, Japan
| | - Thomas Hankeln
- Institute of Organismic and Molecular Evolution, Molecular Genetics & Genome Analysis Group, Johannes Gutenberg University Mainz, J. J. Becher-Weg 30A, Mainz D-55128, Germany.
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13
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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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14
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Zhao J, Zhang X, Li Y, Yu J, Chen Z, Niu Y, Ran S, Wang S, Ye W, Luo Z, Li X, Hao Y, Zong J, Xia C, Xia J, Wu J. Interorgan communication with the liver: novel mechanisms and therapeutic targets. Front Immunol 2023; 14:1314123. [PMID: 38155961 PMCID: PMC10754533 DOI: 10.3389/fimmu.2023.1314123] [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: 10/11/2023] [Accepted: 11/28/2023] [Indexed: 12/30/2023] Open
Abstract
The liver is a multifunctional organ that plays crucial roles in numerous physiological processes, such as production of bile and proteins for blood plasma, regulation of blood levels of amino acids, processing of hemoglobin, clearance of metabolic waste, maintenance of glucose, etc. Therefore, the liver is essential for the homeostasis of organisms. With the development of research on the liver, there is growing concern about its effect on immune cells of innate and adaptive immunity. For example, the liver regulates the proliferation, differentiation, and effector functions of immune cells through various secreted proteins (also known as "hepatokines"). As a result, the liver is identified as an important regulator of the immune system. Furthermore, many diseases resulting from immune disorders are thought to be related to the dysfunction of the liver, including systemic lupus erythematosus, multiple sclerosis, and heart failure. Thus, the liver plays a role in remote immune regulation and is intricately linked with systemic immunity. This review provides a comprehensive overview of the liver remote regulation of the body's innate and adaptive immunity regarding to main areas: immune-related molecules secreted by the liver and the liver-resident cells. Additionally, we assessed the influence of the liver on various facets of systemic immune-related diseases, offering insights into the clinical application of target therapies for liver immune regulation, as well as future developmental trends.
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Affiliation(s)
- Jiulu Zhao
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xi Zhang
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yuan Li
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jizhang Yu
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhang Chen
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yuqing Niu
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shuan Ran
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Song Wang
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Weicong Ye
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zilong Luo
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaohan Li
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yanglin Hao
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Junjie Zong
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Chengkun Xia
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jiahong Xia
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Key Laboratory of Organ Transplantation, Ministry of Education, National Health Commission Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Jie Wu
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Key Laboratory of Organ Transplantation, Ministry of Education, National Health Commission Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
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15
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Lowe KO, Tanase CE, Maghami S, Fisher LE, Ghaemmaghami AM. Inflammatory Network of Liver Fibrosis and How It Can Be Targeted Therapeutically. IMMUNO 2023; 3:375-408. [DOI: 10.3390/immuno3040023] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2025] Open
Abstract
Liver fibrosis is a complex, dynamic process associated with a broad spectrum of chronic liver diseases and acute liver failure, characterised by the dysregulated intrahepatic production of extracellular matrix proteins replacing functional liver cells with scar tissue. Fibrosis progresses due to an interrelated cycle of hepatocellular injury, triggering a persistent wound-healing response. The accumulation of scar tissue and chronic inflammation can eventually lead to cirrhosis and hepatocellular carcinoma. Currently, no therapies exist to directly treat or reverse liver fibrosis; hence, it remains a substantial global disease burden. A better understanding of the intricate inflammatory network that drives the initiation and maintenance of liver fibrosis to enable the rationale design of new intervention strategies is required. This review clarifies the most current understanding of the hepatic fibrosis cellular network with a focus on the role of regulatory T cells, and a possible trajectory for T cell immunotherapy in fibrosis treatment. Despite good progress in elucidating the role of the immune system in liver fibrosis, future work to better define the function of different immune cells and their mediators at different fibrotic stages is needed, which will enhance the development of new therapies.
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Affiliation(s)
- Kirstin O. Lowe
- School of Life Sciences, University of Nottingham, Nottingham NG7 2RD, UK
| | | | - Susan Maghami
- Hull York Medical School, University of York, York YO10 5DD, UK
| | - Leanne E. Fisher
- School of Life Sciences, University of Nottingham, Nottingham NG7 2RD, UK
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16
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Chung KJ, Legaki AI, Papadopoulos G, Gercken B, Gebler J, Schwabe RF, Chavakis T, Chatzigeorgiou A. Analysis of the Role of Stellate Cell VCAM-1 in NASH Models in Mice. Int J Mol Sci 2023; 24:4813. [PMID: 36902241 PMCID: PMC10002755 DOI: 10.3390/ijms24054813] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 02/22/2023] [Accepted: 02/23/2023] [Indexed: 03/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) can progress to non-alcoholic steatohepatitis (NASH), characterized by inflammation and fibrosis. Fibrosis is mediated by hepatic stellate cells (HSC) and their differentiation into activated myofibroblasts; the latter process is also promoted by inflammation. Here we studied the role of the pro-inflammatory adhesion molecule vascular cell adhesion molecule-1 (VCAM-1) in HSCs in NASH. VCAM-1 expression was upregulated in the liver upon NASH induction, and VCAM-1 was found to be present on activated HSCs. We therefore utilized HSC-specific VCAM-1-deficient and appropriate control mice to explore the role of VCAM-1 on HSCs in NASH. However, HSC-specific VCAM-1-deficient mice, as compared to control mice, did not show a difference with regards to steatosis, inflammation and fibrosis in two different models of NASH. Hence, VCAM-1 on HSCs is dispensable for NASH development and progression in mice.
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Affiliation(s)
- Kyoung-Jin Chung
- Institute for Clinical Chemistry and Laboratory Medicine, University Hospital and Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Fetscherstrasse 74, 01307 Dresden, Germany
| | - Aigli-Ioanna Legaki
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias Str., 11527 Athens, Greece
| | - Grigorios Papadopoulos
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias Str., 11527 Athens, Greece
| | - Bettina Gercken
- Institute for Clinical Chemistry and Laboratory Medicine, University Hospital and Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Fetscherstrasse 74, 01307 Dresden, Germany
| | - Janine Gebler
- Institute for Clinical Chemistry and Laboratory Medicine, University Hospital and Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Fetscherstrasse 74, 01307 Dresden, Germany
| | - Robert F. Schwabe
- Department of Medicine, Columbia University, New York, NY 10032, USA
| | - Triantafyllos Chavakis
- Institute for Clinical Chemistry and Laboratory Medicine, University Hospital and Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Fetscherstrasse 74, 01307 Dresden, Germany
| | - Antonios Chatzigeorgiou
- Institute for Clinical Chemistry and Laboratory Medicine, University Hospital and Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Fetscherstrasse 74, 01307 Dresden, Germany
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias Str., 11527 Athens, Greece
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17
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Liu X, Brenner DA, Kisseleva T. Human Hepatic Stellate Cells: Isolation and Characterization. Methods Mol Biol 2023; 2669:221-232. [PMID: 37247063 DOI: 10.1007/978-1-0716-3207-9_13] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/30/2023]
Abstract
Liver fibrosis of different etiologies is characterized by activation of hepatic stellate cells (aHSCs) into collagen type I secreting myofibroblasts, which produce fibrous scar and make the liver fibrotic. aHSCs are the major source of myofibroblasts and, therefore, the primary targets of anti-fibrotic therapy. Despite extensive studies, targeting of aHSCs in patients provides challenges. The progress in anti-fibrotic drug development relies on translational studies but is limited by the availability of primary human HSCs. Here we describe a perfusion/gradient centrifugation-based method of the large-scale isolation of highly purified and viable human HSCs (hHSCs) from normal and diseased human livers and the strategies of hHSC cryopreservation.
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Affiliation(s)
- Xiao Liu
- Department of Medicine, University of California, San Diego School of Medicine, San Diego, CA, USA
- Department of Surgery, University of California, San Diego School of Medicine, San Diego, CA, USA
| | - David A Brenner
- Department of Medicine, University of California, San Diego School of Medicine, San Diego, CA, USA
| | - Tatiana Kisseleva
- Department of Surgery, University of California, San Diego School of Medicine, San Diego, CA, USA.
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18
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Ali E, Trailin A, Ambrozkiewicz F, Liška V, Hemminki K. Activated Hepatic Stellate Cells in Hepatocellular Carcinoma: Their Role as a Potential Target for Future Therapies. Int J Mol Sci 2022; 23:ijms232315292. [PMID: 36499616 PMCID: PMC9741299 DOI: 10.3390/ijms232315292] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Revised: 12/01/2022] [Accepted: 12/02/2022] [Indexed: 12/11/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a global healthcare challenge, which affects more than 815,000 new cases every year. Activated hepatic stellate cells (aHSCs) remain the principal cells that drive HCC onset and growth. aHSCs suppress the anti-tumor immune response through interaction with different immune cells. They also increase the deposition of the extracellular matrix proteins, challenging the reversion of fibrosis and increasing HCC growth and metastasis. Therapy for HCC was reported to activate HSCs, which could explain the low efficacy of current treatments. Conversely, recent studies aimed at the deactivation of HSCs show that they have been able to inhibit HCC growth. In this review article, we discuss the role of aHSCs in HCC pathophysiology and therapy. Finally, we provide suggestions for the experimental implementation of HSCs in HCC therapies.
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Affiliation(s)
- Esraa Ali
- Laboratory of Translational Cancer Genomics, Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Alej Svobody 1665/76, 32300 Pilsen, Czech Republic
| | - Andriy Trailin
- Laboratory of Translational Cancer Genomics, Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Alej Svobody 1665/76, 32300 Pilsen, Czech Republic
- Correspondence: ; Tel.: +420-377-593-862
| | - Filip Ambrozkiewicz
- Laboratory of Translational Cancer Genomics, Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Alej Svobody 1665/76, 32300 Pilsen, Czech Republic
| | - Václav Liška
- Laboratory of Cancer Treatment and Tissue Regeneration, Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Alej Svobody 1665/76, 32300 Pilsen, Czech Republic
- Department of Surgery University Hospital and Faculty of Medicine in Pilsen, Charles University, Alej Svobody 80, 32300 Pilsen, Czech Republic
| | - Kari Hemminki
- Laboratory of Translational Cancer Genomics, Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Alej Svobody 1665/76, 32300 Pilsen, Czech Republic
- Department of Cancer Epidemiology, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
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19
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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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20
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Cassese G, Han HS, Lee B, Lee HW, Cho JY, Panaro F, Troisi RI. Immunotherapy for hepatocellular carcinoma: A promising therapeutic option for advanced disease. World J Hepatol 2022; 14:1862-1874. [PMID: 36340753 PMCID: PMC9627435 DOI: 10.4254/wjh.v14.i10.1862] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Revised: 07/20/2022] [Accepted: 10/03/2022] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide, and its incidence continues to increase. Despite improvements in both medical and surgical therapies, HCC remains associated with poor outcomes due to its high rates of recurrence and mortality. Approximately 50% of patients require systemic therapies that traditionally consist of tyrosine kinase inhibitors. Recently, however, immune checkpoint inhibitors have revolutionized HCC management, providing new therapeutic options. Despite these major advances, the different factors involved in poor clinical responses and molecular pathways leading to resistance following use of these therapies remain unclear. Alternative strategies, such as adoptive T cell transfer, vaccination, and virotherapy, are currently under evaluation. Combinations of immunotherapies with other systemic or local treatments are also being investigated and may be the most promising opportunities for HCC treatment. The aim of this review is to provide updated information on currently available immunotherapies for HCC as well as future perspectives.
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Affiliation(s)
- Gianluca Cassese
- Department of Clinical Medicine and Surgery, Division of Minimally Invasive and Robotic HPB Surgery, Federico II University, Naples 80131, Italy
- Department of Surgery, Seoul National University Bundang Hospital, Seongnam 13620, South Korea
| | - Ho-Seong Han
- Department of Surgery, Seoul National University Bundang Hospital, Seongnam 13620, South Korea.
| | - Boram Lee
- Department of Surgery, Seoul National University Bundang Hospital, Seongnam 13620, South Korea
| | - Hae Won Lee
- Department of Surgery, Seoul National University Bundang Hospital, Seongnam 13620, South Korea
| | - Jai Young Cho
- Department of Surgery, Seoul National University Bundang Hospital, Seongnam 13620, South Korea
| | - Fabrizio Panaro
- Department of Surgery, Division of HBP Surgery and Transplantation, Montpellier University Hospital - School of Medicine, Montpellier 34000, France
| | - Roberto Ivan Troisi
- Department of Clinical Medicine and Surgery, Division of Minimally Invasive and Robotic HPB Surgery, Federico II University, Naples 80131, Italy
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21
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Feng H, Zhuo Y, Zhang X, Li Y, Li Y, Duan X, Shi J, Xu C, Gao Y, Yu Z. Tumor Microenvironment in Hepatocellular Carcinoma: Key Players for Immunotherapy. J Hepatocell Carcinoma 2022; 9:1109-1125. [PMID: 36320666 PMCID: PMC9618253 DOI: 10.2147/jhc.s381764] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Accepted: 10/19/2022] [Indexed: 11/06/2022] Open
Abstract
Hepatocellular carcinoma (HCC) remains a serious medical therapeutic challenge as conventional curative avenues such as surgery and chemotherapy only benefit for few patients with limited tumor burden. Immunotherapy achieves clinical progress in the treatment of this prevalent malignant disease by virtue of the development of tumor immunology; however, most patients have experienced minimal or no clinical benefit in terms of overall survival. The complexity and diversity of tumor microenvironment (TME) built by immune and stromal cell subsets has been considered to be responsible for the insufficiency of immunotherapy. The advance of bioanalytical technology boosts the exploration of the composition and differentiation of these infiltrated cells, which reflect the immune state of the TME and impact the efficacy of the antitumor immune response. Targeting these cells to remodel the TME is one of the important immunotherapeutic approaches to improve HCC treatment. In this review, we focused on the role of these non-cancerous cells in the tumor progression, and elaborated their function on cancer immunotherapy when manipulating them as potential targets.
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Affiliation(s)
- Hai Feng
- Institute of Infectious Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China
| | - Yunhui Zhuo
- Department of Liver Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China
| | - Xuemei Zhang
- Department of Liver Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China
| | - Yuyao Li
- Institute of Infectious Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China
| | - Yue Li
- Institute of Infectious Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China
| | - Xiangjuan Duan
- Department of Liver Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China
| | - Jia Shi
- Institute of Infectious Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China
| | - Chengbin Xu
- Department of Informatics, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China
| | - Yueqiu Gao
- Institute of Infectious Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China,Department of Liver Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China,Correspondence: Yueqiu Gao, Institute of Infectious Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China, Tel +86 21 20256507, Fax +86 21 20256699, Email
| | - Zhuo Yu
- Department of Liver Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China,Zhuo Yu, Department of Liver Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China, Tel +86 21 20256507, Fax +86 21 20256699, Email
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22
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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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23
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Elchaninov A, Vishnyakova P, Menyailo E, Sukhikh G, Fatkhudinov T. An Eye on Kupffer Cells: Development, Phenotype and the Macrophage Niche. Int J Mol Sci 2022; 23:9868. [PMID: 36077265 PMCID: PMC9456487 DOI: 10.3390/ijms23179868] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Revised: 08/14/2022] [Accepted: 08/29/2022] [Indexed: 11/16/2022] Open
Abstract
Macrophages are key participants in the maintenance of tissue homeostasis under normal and pathological conditions, and implement a rich diversity of functions. The largest population of resident tissue macrophages is found in the liver. Hepatic macrophages, termed Kupffer cells, are involved in the regulation of multiple liver functionalities. Specific differentiation profiles and functional activities of tissue macrophages have been attributed to the shaping role of the so-called tissue niche microenvironments. The fundamental macrophage niche concept was lately shaken by a flood of new data, leading to a revision and substantial update of the concept, which constitutes the main focus of this review. The macrophage community discusses contemporary evidence on the developmental origins of resident macrophages, notably Kupffer cells and the issues of heterogeneity of the hepatic macrophage populations, as well as the roles of proliferation, cell death and migration processes in the maintenance of macrophage populations of the liver. Special consideration is given to interactions of Kupffer cells with other local cell lineages, including Ito cells, sinusoidal endothelium and hepatocytes, which participate in the maintenance of their phenotypical and functional identity.
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Affiliation(s)
- Andrey Elchaninov
- Laboratory of Regenerative Medicine, National Medical Research Center for Obstetrics, Gynecology and Perinatology Named after Academician V.I. Kulakov of Ministry of Healthcare of Russian Federation, 117997 Moscow, Russia
- Histology Department, Pirogov Russian National Research Medical University, 117997 Moscow, Russia
| | - Polina Vishnyakova
- Laboratory of Regenerative Medicine, National Medical Research Center for Obstetrics, Gynecology and Perinatology Named after Academician V.I. Kulakov of Ministry of Healthcare of Russian Federation, 117997 Moscow, Russia
- Histology Department, Medical Institute, Peoples’ Friendship University of Russia, 117198 Moscow, Russia
| | - Egor Menyailo
- Laboratory of Growth and Development, Avtsyn Research Institute of Human Morphology of FSBI “Petrovsky National Research Centre of Surgery”, 117418 Moscow, Russia
| | - Gennady Sukhikh
- Laboratory of Regenerative Medicine, National Medical Research Center for Obstetrics, Gynecology and Perinatology Named after Academician V.I. Kulakov of Ministry of Healthcare of Russian Federation, 117997 Moscow, Russia
| | - Timur Fatkhudinov
- Histology Department, Medical Institute, Peoples’ Friendship University of Russia, 117198 Moscow, Russia
- Laboratory of Growth and Development, Avtsyn Research Institute of Human Morphology of FSBI “Petrovsky National Research Centre of Surgery”, 117418 Moscow, Russia
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24
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Carter JK, Friedman SL. Hepatic Stellate Cell-Immune Interactions in NASH. Front Endocrinol (Lausanne) 2022; 13:867940. [PMID: 35757404 PMCID: PMC9218059 DOI: 10.3389/fendo.2022.867940] [Citation(s) in RCA: 50] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Accepted: 04/29/2022] [Indexed: 02/06/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the dominant cause of liver disease worldwide. Nonalcoholic steatohepatitis (NASH), a more aggressive presentation of NAFLD, is characterized by severe hepatocellular injury, inflammation, and fibrosis. Chronic inflammation and heightened immune cell activity have emerged as hallmark features of NASH and key drivers of fibrosis through the activation of hepatic stellate cells (HSCs). Recent advances in our understanding of the molecular and cellular pathways in NASH have highlighted extensive crosstalk between HSCs and hepatic immune populations that strongly influences disease activity. Here, we review these findings, emphasizing the roles of HSCs in liver immunity and inflammation, key cell-cell interactions, and exciting areas for future investigation.
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Affiliation(s)
- James K Carter
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, United States
- Medical Scientist Training Program, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Scott L Friedman
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, United States
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25
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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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26
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Cho HJ, Cheong JY. Role of Immune Cells in Patients with Hepatitis B Virus-Related Hepatocellular Carcinoma. Int J Mol Sci 2021; 22:ijms22158011. [PMID: 34360777 PMCID: PMC8348470 DOI: 10.3390/ijms22158011] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 07/23/2021] [Accepted: 07/23/2021] [Indexed: 12/17/2022] Open
Abstract
Hepatocellular carcinoma (HCC) develops almost entirely in the presence of chronic inflammation. Chronic hepatitis B virus (HBV) infection with recurrent immune-mediated liver damage ultimately leads to cirrhosis and HCC. It is widely accepted that HBV infection induces the dysfunction of the innate and adaptive immune responses that engage various immune cells. Natural killer (NK) cells are associated with early antiviral and antitumor properties. On the other hand, inflammatory cells release various cytokines and chemokines that may promote HCC tumorigenesis. Moreover, immunosuppressive cells such as regulatory T cells (Treg) and myeloid-derived suppressive cells play a critical role in hepatocarcinogenesis. HBV-specific CD8+ T cells have been identified as pivotal players in antiviral responses, whilst extremely activated CD8+ T cells induce enormous inflammatory responses, and chronic inflammation can facilitate hepatocarcinogenesis. Controlling and maintaining the balance in the immune system is an important aspect in the management of HBV-related HCC. We conducted a review of the current knowledge on the immunopathogenesis of HBV-induced inflammation and the role of such immune activation in the tumorigenesis of HCC based on the recent studies on innate and adaptive immune cell dysfunction in HBV-related HCC.
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Affiliation(s)
| | - Jae-Youn Cheong
- Correspondence: ; Tel.: +82-31-219-6939; Fax: +82-31-219-5999
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27
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Sufleţel RT, Melincovici CS, Gheban BA, Toader Z, Mihu CM. Hepatic stellate cells - from past till present: morphology, human markers, human cell lines, behavior in normal and liver pathology. ROMANIAN JOURNAL OF MORPHOLOGY AND EMBRYOLOGY 2021; 61:615-642. [PMID: 33817704 PMCID: PMC8112759 DOI: 10.47162/rjme.61.3.01] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
Hepatic stellate cell (HSC), initially analyzed by von Kupffer, in 1876, revealed to be an extraordinary mesenchymal cell, essential for both hepatocellular function and lesions, being the hallmark of hepatic fibrogenesis and carcinogenesis. Apart from their implications in hepatic injury, HSCs play a vital role in liver development and regeneration, xenobiotic response, intermediate metabolism, and regulation of immune response. In this review, we discuss the current state of knowledge regarding HSCs morphology, human HSCs markers and human HSC cell lines. We also summarize the latest findings concerning their roles in normal and liver pathology, focusing on their impact in fibrogenesis, chronic viral hepatitis and liver tumors.
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Affiliation(s)
- Rada Teodora Sufleţel
- Discipline of Histology, Department of Morphological Sciences, Iuliu Haţieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania;
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28
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Grand M, Waqasi M, Demarta-Gatsi C, Wei Y, Peronet R, Commere PH, Puig A, Axelrod J, Caldelari R, Heussler V, Amino R, Mecheri S. Hepatic Inflammation Confers Protective Immunity Against Liver Stages of Malaria Parasite. Front Immunol 2020; 11:585502. [PMID: 33329563 PMCID: PMC7710885 DOI: 10.3389/fimmu.2020.585502] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Accepted: 10/13/2020] [Indexed: 12/21/2022] Open
Abstract
Deciphering the mechanisms by which Plasmodium parasites develop inside hepatocytes is an important step toward the understanding of malaria pathogenesis. We propose that the nature and the magnitude of the inflammatory response in the liver are key for the establishment of the infection. Here, we used mice deficient in the multidrug resistance-2 gene (Mdr2-/-)-encoded phospholipid flippase leading to the development of liver inflammation. Infection of Mdr2-/- mice with Plasmodium berghei ANKA (PbANKA) sporozoites (SPZ) resulted in the blockade of hepatic exo-erythrocytic forms (EEFs) with no further development into blood stage parasites. Interestingly, cultured primary hepatocytes from mutant and wild-type mice are equally effective in supporting EEF development. The abortive infection resulted in a long-lasting immunity in Mdr2-/- mice against infectious SPZ where neutrophils and IL-6 appear as key effector components along with CD8+ and CD4+ effector and central memory T cells. Inflammation-induced breakdown of liver tolerance promotes anti-parasite immunity and provides new approaches for the design of effective vaccines against malaria disease.
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Affiliation(s)
- Morgane Grand
- Institut Pasteur, Unité de Biologie des Interactions Hôte Parasites, Paris, France
- CNRS ERL9195, Paris, France
- INSERM U1201, Paris, France
- Collège Doctoral, Sorbonne Université, Paris, France
| | - Mishelle Waqasi
- Institut Pasteur, Unité de Biologie des Interactions Hôte Parasites, Paris, France
- CNRS ERL9195, Paris, France
- INSERM U1201, Paris, France
| | - Claudia Demarta-Gatsi
- Institut Pasteur, Unité de Biologie des Interactions Hôte Parasites, Paris, France
- CNRS ERL9195, Paris, France
- INSERM U1201, Paris, France
| | - Yu Wei
- Institut Pasteur of Shanghai, Chinese Academy of Sciences, University of Chinese Academy of Sciences, CAS Key Laboratory of Molecular Virology and Immunology, Shanghai, China
- Institut Pasteur, Unité de Virologie Moléculaire et Vaccinologie, Paris, France
| | - Roger Peronet
- Institut Pasteur, Unité de Biologie des Interactions Hôte Parasites, Paris, France
- CNRS ERL9195, Paris, France
- INSERM U1201, Paris, France
| | | | - Amandine Puig
- Institut Pasteur, Unité de Biologie des Interactions Hôte Parasites, Paris, France
- CNRS ERL9195, Paris, France
- INSERM U1201, Paris, France
| | - Jonathan Axelrod
- Goldyne Savad Institute of Gene Therapy, Hadassah Medical Organization, Jerusalem, Israel
| | - Reto Caldelari
- Institute of Cell Biology, University of Bern, Bern, Switzerland
| | - Volker Heussler
- Institute of Cell Biology, University of Bern, Bern, Switzerland
| | - Rogerio Amino
- Institut Pasteur, Malaria Infection and Immunity Unit, Paris, France
| | - Salaheddine Mecheri
- Institut Pasteur, Unité de Biologie des Interactions Hôte Parasites, Paris, France
- CNRS ERL9195, Paris, France
- INSERM U1201, Paris, France
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29
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Drescher HK, Bartsch LM, Weiskirchen S, Weiskirchen R. Intrahepatic T H17/T Reg Cells in Homeostasis and Disease-It's All About the Balance. Front Pharmacol 2020; 11:588436. [PMID: 33123017 PMCID: PMC7566778 DOI: 10.3389/fphar.2020.588436] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Accepted: 09/15/2020] [Indexed: 12/14/2022] Open
Abstract
Both acute and chronic hepatic inflammation likely result from an imbalance in the TH1/TH2 cell response and can lead to liver fibrosis and end-stage liver disease. More recently, a novel CD4+ T helper cell subset was described, characterized by the production of IL-17 and IL-22. These TH17 cells 50were predominantly implicated in host defense against infections and in autoimmune diseases. Interestingly, studies over the last 10 years revealed that the development of TH17 cells favors pro-inflammatory responses in almost all tissues and there is a reciprocal relationship between TH17 and TReg cells. The balance between TH17and TReg cells is critical for immune reactions, especially in injured liver tissue and the return to immune homeostasis. The pathogenic contribution of TH17 and TReg cells in autoimmunity, acute infection, and chronic liver injury is diverse and varies among disease etiologies. Understanding the mechanisms underlying TH17 cell development, recruitment, and maintenance, along with the suppression of TReg cells, will inform the development of new therapeutic strategies in liver diseases. Active manipulation of the balance between pathogenic and regulatory processes in the liver may assist in the restoration of homeostasis, especially in hepatic inflammation.
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Affiliation(s)
- Hannah K Drescher
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
| | - Lea M Bartsch
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
| | - Sabine Weiskirchen
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), University Hospital, RWTH Aachen, Aachen, Germany
| | - Ralf Weiskirchen
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), University Hospital, RWTH Aachen, Aachen, Germany
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30
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Richardson N, Ng STH, Wraith DC. Antigen-Specific Immunotherapy for Treatment of Autoimmune Liver Diseases. Front Immunol 2020; 11:1586. [PMID: 32793226 PMCID: PMC7385233 DOI: 10.3389/fimmu.2020.01586] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2020] [Accepted: 06/15/2020] [Indexed: 12/11/2022] Open
Abstract
The liver is a critical organ in controlling immune tolerance. In particular, it is now clear that targeting antigens for presentation by antigen presenting cells in the liver can induce immune tolerance to either autoantigens from the liver itself or tissues outside of the liver. Here we review immune mechanisms active within the liver that contribute both to the control of infectious diseases and tolerance to self-antigens. Despite its extraordinary capacity for tolerance induction, the liver remains a target organ for autoimmune diseases. In this review, we compare and contrast known autoimmune diseases of the liver. Currently patients tend to receive strong immunosuppressive treatments and, in many cases, these treatments are associated with deleterious side effects, including a significantly higher risk of infection and associated health complications. We propose that, in future, antigen-specific immunotherapies are adopted for treatment of liver autoimmune diseases in order to avoid such adverse effects. We describe various therapeutic approaches that either are in or close to the clinic, highlight their mechanism of action and assess their suitability for treatment of autoimmune liver diseases.
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Affiliation(s)
| | | | - David C. Wraith
- Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom
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31
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Fisicaro P, Barili V, Rossi M, Montali I, Vecchi A, Acerbi G, Laccabue D, Zecca A, Penna A, Missale G, Ferrari C, Boni C. Pathogenetic Mechanisms of T Cell Dysfunction in Chronic HBV Infection and Related Therapeutic Approaches. Front Immunol 2020; 11:849. [PMID: 32477347 PMCID: PMC7235343 DOI: 10.3389/fimmu.2020.00849] [Citation(s) in RCA: 97] [Impact Index Per Article: 19.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Accepted: 04/14/2020] [Indexed: 12/12/2022] Open
Abstract
A great effort of research has been devoted in the last few years to developing new anti-HBV therapies of finite duration that also provide effective sustained control of virus replication and antigen production. Among the potential therapeutic strategies, immune-modulation represents a promising option to cure HBV infection and the adaptive immune response is a rational target for novel therapeutic interventions, in consideration of the key role played by T cells in the control of virus infections. HBV-specific T cells are severely dysfunctional in chronic HBV infection as a result of several inhibitory mechanisms which are simultaneously active within the chronically inflamed liver. Indeed, the liver is a tolerogenic organ harboring different non-parenchymal cell populations which can serve as antigen presenting cells (APC) but are poorly efficient in effector T cell priming, with propensity to induce T cell tolerance rather than T cell activation, because of a poor expression of co-stimulatory molecules, up-regulation of the co-inhibitory ligands PD-L1 and PD-L2 upon IFN stimulation, and production of immune regulatory cytokines, such as IL10 and TGF-β. They include resident dendritic cells (DCs), comprising myeloid and plasmacytoid DCs, liver sinusoidal endothelial cells (LSECs), Kupffer cells (KCs), hepatic stellate cells (HSCs) as well as the hepatocytes themselves. Additional regulatory mechanisms which contribute to T cell attrition in the chronically infected liver are the high levels of soluble mediators, such as arginase, indoleamine 2,3-dioxygenase (IDO) and suppressive cytokines, the up-regulation of inhibitory checkpoint receptor/ligand pairs, the expansion of regulatory cells, such as CD4+FOXp3+ Treg cells, myeloid-derived suppressor cells and NK cells. This review will deal with the interactions between immune cells and liver environment discussing the different mechanisms which contribute to T cell dysfunction in chronic hepatitis B, some of which are specifically activated in HBV infection and others which are instead common to chronic inflammatory liver diseases in general. Therapeutic interventions targeting dysregulated pathways and cellular functions will be also delineated.
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Affiliation(s)
- Paola Fisicaro
- Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy.,Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Valeria Barili
- Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy.,Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Marzia Rossi
- Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy.,Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Ilaria Montali
- Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy
| | - Andrea Vecchi
- Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy
| | - Greta Acerbi
- Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy.,Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Diletta Laccabue
- Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy
| | - Alessandra Zecca
- Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy
| | - Amalia Penna
- Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy
| | - Gabriele Missale
- Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy.,Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Carlo Ferrari
- Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy.,Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Carolina Boni
- Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy
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32
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Haaker MW, Vaandrager AB, Helms JB. Retinoids in health and disease: A role for hepatic stellate cells in affecting retinoid levels. Biochim Biophys Acta Mol Cell Biol Lipids 2020; 1865:158674. [PMID: 32105672 DOI: 10.1016/j.bbalip.2020.158674] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2019] [Revised: 02/20/2020] [Accepted: 02/21/2020] [Indexed: 12/13/2022]
Abstract
Vitamin A (retinol) is important for normal growth, vision and reproduction. It has a role in the immune response and the development of metabolic syndrome. Most of the retinol present in the body is stored as retinyl esters within lipid droplets in hepatic stellate cells (HSCs). In case of liver damage, HSCs release large amounts of stored retinol, which is partially converted to retinoic acid (RA). This surge of RA can mediate the immune response and enhance the regeneration of the liver. If the damage persists activated HSCs change into myofibroblast-like cells producing extracellular matrix, which increases the chance of tumorigenesis to occur. RA has been shown to decrease proliferation and metastasis of hepatocellular carcinoma. The levels of RA and RA signaling are influenced by the possibility to esterify retinol towards retinyl esters. This suggests a complex regulation between different retinoids, with an important regulatory role for HSCs.
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Affiliation(s)
- Maya W Haaker
- Department of Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, the Netherlands
| | - Arie B Vaandrager
- Department of Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, the Netherlands
| | - J Bernd Helms
- Department of Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, the Netherlands.
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33
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Boeijen LL, Spaan M, Boonstra A. The effects of nucleoside/nucleotide analogues on host immune cells: the baseline for future immune therapy for HBV? Antivir Ther 2020; 25:181-191. [PMID: 32589166 DOI: 10.3851/imp3364] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/30/2020] [Indexed: 02/07/2023]
Abstract
HBV is a non-cytopathic virus and the progression of liver fibrosis is attributed to the host immune response. Complete suppression of viral replication using nucleotide or nucleoside analogues (NUCs) can prevent most complications related to chronic HBV infection. Unfortunately, antiviral treatment has to be administered lifelong to the majority of patients as HBV persists in the hepatocytes. However, although NUCs are very frequently administered in clinical practice, their effects on vital parts of the host immune response to HBV are not well established. In this review we summarize the currently available data gathered from longitudinal studies that investigated treatment-associated alterations of HBV-specific CD4+ and CD8+ T-cells, regulatory T-cells and natural killer (NK) cells. These observations are important, as they can guide the design of studies that investigate the efficacy of new immune therapeutic agents. Novel experimental compounds will likely be added to ongoing NUC treatment, which leads to a functional cure in only a small minority of patients.
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Affiliation(s)
- Lauke L Boeijen
- Department of Gastroenterology and Hepatology, Erasmus MC, Rotterdam, the Netherlands
| | - Michelle Spaan
- Department of Gastroenterology and Hepatology, Erasmus MC, Rotterdam, the Netherlands
| | - André Boonstra
- Department of Gastroenterology and Hepatology, Erasmus MC, Rotterdam, the Netherlands
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34
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Liu J, Kong D, Qiu J, Xie Y, Lu Z, Zhou C, Liu X, Zhang R, Wang Y. Praziquantel ameliorates CCl 4 -induced liver fibrosis in mice by inhibiting TGF-β/Smad signalling via up-regulating Smad7 in hepatic stellate cells. Br J Pharmacol 2019; 176:4666-4680. [PMID: 31412137 DOI: 10.1111/bph.14831] [Citation(s) in RCA: 72] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2018] [Revised: 06/24/2019] [Accepted: 08/08/2019] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND AND PURPOSE Praziquantel is a schistosomicide, which has been used for more than 30 years due to its efficiency, safety, and mild side effects. Previous studies showed that prolonged treatment with praziquantel suppressed the development of liver fibrosis in mice with schistosomiasis. In this study, we investigated the potential mechanisms underlying the antifibrotic effects of praziquantel. EXPERIMENTAL APPROACH To avoid the effect of schistosomicidal activity of praziquantel against liver fibrosis induced by Schistosoma japonicum infection, we established a mouse model of carbon tetrachloride (CCl4 )-induced liver fibrosis for in vivo studies and used TGF-β1-stimulated human hepatic stellate cell line (LX-2) in addition to other fibroblast-like cell line (MES13) and fibroblast cell line (NIH3T3) in vitro. Western blotting, immunohistochemistry, quantitative real-time PCR, siRNA, and immunofluorescence staining were utilized to assess the expression of key molecules in liver fibrosis and the TGF-β/Smad pathway. KEY RESULTS Praziquantel significantly attenuated CCl4 -induced liver fibrosis by inhibiting the activation of hepatic stellate cells (HSCs) and expression of collagen matrix via enhancement of Smad7 expression, which were confirmed in LX-2, MES13, and NIH3T3 cells in vitro. In contrast, knockdown of Smad7 in LX-2 cells prevented praziquantel-mediated inhibition of LX-2 cell activation and TGF-β1-mediated collagen type I α1 induction, revealing the critical role of Smad7 in the antifibrotic effect of praziquantel during liver fibrosis. CONCLUSIONS AND IMPLICATIONS PZQ exhibited a strong efficacy against liver fibrosis by inhibiting activation of HSCs via Smad7 up-regulation, suggesting potential broad utility in treatment of diseases characterized by liver fibrosis.
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Affiliation(s)
- Jinfeng Liu
- Department of Pathogen Biology, Key Laboratory of Pathogen Biology of Jiangsu Province, Nanjing Medical University, Nanjing, China
| | - Delong Kong
- Department of Pathogen Biology, Key Laboratory of Pathogen Biology of Jiangsu Province, Nanjing Medical University, Nanjing, China.,Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Laboratory of Infection and Immunity, Xuzhou Medical University, Xuzhou, China
| | - Jingfan Qiu
- Department of Pathogen Biology, Key Laboratory of Pathogen Biology of Jiangsu Province, Nanjing Medical University, Nanjing, China
| | - Yanci Xie
- Department of Pathogen Biology, Key Laboratory of Pathogen Biology of Jiangsu Province, Nanjing Medical University, Nanjing, China
| | - Zhongkui Lu
- Department of Pathogen Biology, Key Laboratory of Pathogen Biology of Jiangsu Province, Nanjing Medical University, Nanjing, China
| | - Chunlei Zhou
- Department of Pathogen Biology, Key Laboratory of Pathogen Biology of Jiangsu Province, Nanjing Medical University, Nanjing, China.,Department of Pathology, Nanjing Children's Hospital, Nanjing, China
| | - Xinjian Liu
- Department of Pathogen Biology, Key Laboratory of Pathogen Biology of Jiangsu Province, Nanjing Medical University, Nanjing, China
| | - Rong Zhang
- Department of Pathogen Biology, Key Laboratory of Pathogen Biology of Jiangsu Province, Nanjing Medical University, Nanjing, China
| | - Yong Wang
- Department of Pathogen Biology, Key Laboratory of Pathogen Biology of Jiangsu Province, Nanjing Medical University, Nanjing, China.,Department of Pathogen Biology and Immunology, Kangda College, Nanjing Medical University, Lianyungang, China.,Key Laboratory of Infectious Diseases, School of Public Health, Nanjing Medical University, Nanjing, China
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Kisseleva T, Brenner DA. The Crosstalk between Hepatocytes, Hepatic Macrophages, and Hepatic Stellate Cells Facilitates Alcoholic Liver Disease. Cell Metab 2019; 30:850-852. [PMID: 31693880 DOI: 10.1016/j.cmet.2019.10.010] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Choi et al. (2019) explored the pathogenesis of alcohol-induced de novo lipogenesis in mice with ALD to reveal a novel mechanism of cannabinoid 1 receptor (CB1R)-SREB1-dependent triglyceride synthesis that requires crosstalk between hepatocytes and HSCs. Using genetic and pharmacological inhibition of the key components of the xCT-glutamate→mGluR5-2-AG→CB1R-SREBP1-FASN paracrine communication system, Choi et al. identified potential new targets for drugs for ALD.
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Affiliation(s)
- Tatiana Kisseleva
- Department of Surgery, University of California, San Diego, San Diego, CA 92093, USA.
| | - David A Brenner
- Department of Medicine, University of California, San Diego, San Diego, CA 92093, USA.
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36
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Mooney B, Torres‐Velez FJ, Doering J, Ehrbar DJ, Mantis NJ. Sensitivity of Kupffer cells and liver sinusoidal endothelial cells to ricin toxin and ricin toxin-Ab complexes. J Leukoc Biol 2019; 106:1161-1176. [PMID: 31313388 PMCID: PMC7008010 DOI: 10.1002/jlb.4a0419-123r] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2019] [Revised: 06/03/2019] [Accepted: 07/02/2019] [Indexed: 12/11/2022] Open
Abstract
Ricin toxin is a plant-derived, ribosome-inactivating protein that is rapidly cleared from circulation by Kupffer cells (KCs) and liver sinusoidal endothelial cells (LSECs)-with fatal consequences. Rather than being inactivated, ricin evades normal degradative pathways and kills both KCs and LSECs with remarkable efficiency. Uptake of ricin by these 2 specialized cell types in the liver occurs by 2 parallel routes: a "lactose-sensitive" pathway mediated by ricin's galactose/N-acetylgalactosamine-specific lectin subunit (RTB), and a "mannose-sensitive" pathway mediated by the mannose receptor (MR; CD206) or other C-type lectins capable of recognizing the mannose-side chains displayed on ricin's A (RTA) and B subunits. In this report, we investigated the capacity of a collection of ricin-specific mouse MAb and camelid single-domain (VH H) antibodies to protect KCs and LSECs from ricin-induced killing. In the case of KCs, individual MAbs against RTA or RTB afforded near complete protection against ricin in ex vivo and in vivo challenge studies. In contrast, individual MAbs or VH Hs afforded little (<40%) or even no protection to LSECs against ricin-induced death. Complete protection of LSECs was only achieved with MAb or VH H cocktails, with the most effective mixtures targeting RTA and RTB simultaneously. Although the exact mechanisms of protection of LSECs remain unknown, evidence indicates that the Ab cocktails exert their effects on the mannose-sensitive uptake pathway without the need for Fcγ receptor involvement. In addition to advancing our understanding of how toxins and small immune complexes are processed by KCs and LSECs, our study has important implications for the development of Ab-based therapies designed to prevent or treat ricin exposure should the toxin be weaponized.
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Affiliation(s)
- Bridget Mooney
- Division of Infectious DiseasesWadsworth CenterNew York State Department of HealthAlbanyNew YorkUSA
| | - Fernando J. Torres‐Velez
- Division of Infectious DiseasesWadsworth CenterNew York State Department of HealthAlbanyNew YorkUSA
| | - Jennifer Doering
- Division of Infectious DiseasesWadsworth CenterNew York State Department of HealthAlbanyNew YorkUSA
| | - Dylan J. Ehrbar
- Division of Infectious DiseasesWadsworth CenterNew York State Department of HealthAlbanyNew YorkUSA
| | - Nicholas J. Mantis
- Division of Infectious DiseasesWadsworth CenterNew York State Department of HealthAlbanyNew YorkUSA
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Abstract
Invariant natural killer T cells (iNKT cells) are an innate-like T cell subset that expresses an invariant T cell receptor (TCR) α-chain and recognizes lipids presented on CD1d. They secrete diverse cytokines and can influence many types of immune responses. Despite having highly similar TCR specificities, iNKT cells differentiate in the thymus into distinct subsets that are analogous to T helper 1 (TH1), TH2 and TH17 cell subsets. Additional iNKT cell subsets that may require peripheral activation have also been described, including one that produces IL-10. In general, iNKT cells are non-circulating, tissue-resident lymphocytes, but the prevalence of different iNKT cell subsets differs markedly between tissues. Here, we summarize the functions of iNKT cells in four tissues in which they are prevalent, namely, the liver, the lungs, adipose tissue and the intestine. Importantly, we explain how local iNKT cell responses at each site contribute to tissue homeostasis and protection from infection but can also contribute to tissue inflammation and damage.
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38
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Zhang B, Liu Y, Wang X, Li J, Xu X, Guo L, Ho WZ. TLR3 Activation of Hepatic Stellate Cell Line Suppresses HBV Replication in HepG2 Cells. Front Immunol 2018; 9:2921. [PMID: 30619284 PMCID: PMC6304368 DOI: 10.3389/fimmu.2018.02921] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2018] [Accepted: 11/28/2018] [Indexed: 12/23/2022] Open
Abstract
There is limited information about the role of hepatic stellate cells (HSCs) in the liver innate immunity against hepatitis B virus (HBV) infection. We thus examined whether hepatic stellate cell line (LX-2) can be immunologically activated and produce antiviral factors that inhibit HBV replication in HepG2 cells. We found that LX-2 cells expressed the functional Toll-like receptor 3 (TLR3), activation of which by PolyI:C resulted in the selective induction of interferon-β (IFN-β) and IFN-λs, the phosphorylation of IFN regulatory factor 3 (IRF3) and IRF7. When HepG2 cells were treated with supernatant (SN) from PolyI:C-activated LX-2 cells, HBV replication was significantly inhibited. IFN-β and IFN-λ appeared to contribute to LX-2 SN-mediated HBV inhibition, as the antibodies to IFN-β and IFN-λ receptors could largely block the LX-2 SN action. Mechanistically, LX-2 SN treatment of the HepG2 cells induced a number of antiviral IFN-stimulated genes (ISGs: ISG20, ISG54, ISG56, OAS-1, Trim22, and Trim25) and facilitated the phosphorylation of STATs. These observations support further studies on the role of HSCs in the liver innate immunity against HBV infection.
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Affiliation(s)
- Biao Zhang
- School of Basic Medical Sciences, Wuhan University, Wuhan, China
| | - Yu Liu
- School of Basic Medical Sciences, Wuhan University, Wuhan, China
| | - Xu Wang
- Department of Pathology and Laboratory Medicine, Temple University Lewis Katz School of Medicine, Philadelphia, PA, United States
| | - Jieliang Li
- Department of Pathology and Laboratory Medicine, Temple University Lewis Katz School of Medicine, Philadelphia, PA, United States
| | - Xiqiu Xu
- School of Basic Medical Sciences, Wuhan University, Wuhan, China
| | - Le Guo
- School of Basic Medical Sciences, Wuhan University, Wuhan, China
| | - Wen-Zhe Ho
- School of Basic Medical Sciences, Wuhan University, Wuhan, China.,Department of Pathology and Laboratory Medicine, Temple University Lewis Katz School of Medicine, Philadelphia, PA, United States
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Castro PR, Barbosa AS, Pereira JM, Ranfley H, Felipetto M, Gonçalves CAX, Paiva IR, Berg BB, Barcelos LS. Cellular and Molecular Heterogeneity Associated with Vessel Formation Processes. BIOMED RESEARCH INTERNATIONAL 2018; 2018:6740408. [PMID: 30406137 PMCID: PMC6199857 DOI: 10.1155/2018/6740408] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/01/2018] [Accepted: 09/06/2018] [Indexed: 12/11/2022]
Abstract
The microvasculature heterogeneity is a complex subject in vascular biology. The difficulty of building a dynamic and interactive view among the microenvironments, the cellular and molecular heterogeneities, and the basic aspects of the vessel formation processes make the available knowledge largely fragmented. The neovascularisation processes, termed vasculogenesis, angiogenesis, arteriogenesis, and lymphangiogenesis, are important to the formation and proper functioning of organs and tissues both in the embryo and the postnatal period. These processes are intrinsically related to microvascular cells, such as endothelial and mural cells. These cells are able to adjust their activities in response to the metabolic and physiological requirements of the tissues, by displaying a broad plasticity that results in a significant cellular and molecular heterogeneity. In this review, we intend to approach the microvasculature heterogeneity in an integrated view considering the diversity of neovascularisation processes and the cellular and molecular heterogeneity that contribute to microcirculatory homeostasis. For that, we will cover their interactions in the different blood-organ barriers and discuss how they cooperate in an integrated regulatory network that is controlled by specific molecular signatures.
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Affiliation(s)
- Pollyana Ribeiro Castro
- Department of Physiology and Biophysics, Instituto de Ciências Biológicas (ICB), Universidade Federal de Minas Gerais (UFMG), Brazil
| | - Alan Sales Barbosa
- Department of Physiology and Biophysics, Instituto de Ciências Biológicas (ICB), Universidade Federal de Minas Gerais (UFMG), Brazil
| | - Jousie Michel Pereira
- Department of Physiology and Biophysics, Instituto de Ciências Biológicas (ICB), Universidade Federal de Minas Gerais (UFMG), Brazil
| | - Hedden Ranfley
- Department of Physiology and Biophysics, Instituto de Ciências Biológicas (ICB), Universidade Federal de Minas Gerais (UFMG), Brazil
| | - Mariane Felipetto
- Department of Physiology and Biophysics, Instituto de Ciências Biológicas (ICB), Universidade Federal de Minas Gerais (UFMG), Brazil
| | - Carlos Alberto Xavier Gonçalves
- Department of Biochemistry and Immunology, Instituto de Ciências Biológicas (ICB), Universidade Federal de Minas Gerais (UFMG), Brazil
| | - Isabela Ribeiro Paiva
- Department of Pharmacology, Instituto de Ciências Biológicas (ICB), Universidade Federal de Minas Gerais (UFMG), Brazil
| | - Bárbara Betônico Berg
- Department of Pharmacology, Instituto de Ciências Biológicas (ICB), Universidade Federal de Minas Gerais (UFMG), Brazil
| | - Luciola Silva Barcelos
- Department of Physiology and Biophysics, Instituto de Ciências Biológicas (ICB), Universidade Federal de Minas Gerais (UFMG), Brazil
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40
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Role of hepatic stellate cell (HSC)-derived cytokines in hepatic inflammation and immunity. Cytokine 2018; 124:154542. [PMID: 30241896 DOI: 10.1016/j.cyto.2018.09.004] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2018] [Revised: 09/01/2018] [Accepted: 09/07/2018] [Indexed: 12/15/2022]
Abstract
In their quiescent state, Hepatic stellate cells (HSCs), are present in the sub-endothelial space of Disse and have minimal interaction with immune cells. However, upon activation following injury, HSCs directly or indirectly interact with various immune cells that enter the space of Disse and thereby regulate diverse hepatic function and immune physiology. Other than the normal physiological functions of HSCs such as hepatic homeostasis, maturation and differentiation, they also participate in hepatic inflammation by releasing a battery of inflammatory cytokines and chemokines and interacting with other liver cells. Here, we have reviewed the role of HSC in the pathogenesis of liver inflammation and some infectious diseases in order to understand how the interplay between immune cells and HSCs regulates the overall outcome and disease pathology.
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41
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Bobowski-Gerard M, Zummo FP, Staels B, Lefebvre P, Eeckhoute J. Retinoids Issued from Hepatic Stellate Cell Lipid Droplet Loss as Potential Signaling Molecules Orchestrating a Multicellular Liver Injury Response. Cells 2018; 7:cells7090137. [PMID: 30217095 PMCID: PMC6162435 DOI: 10.3390/cells7090137] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2018] [Revised: 09/11/2018] [Accepted: 09/13/2018] [Indexed: 02/08/2023] Open
Abstract
Hepatic stellate cells (HSCs) serve as the main body storage compartment for vitamin A through retinyl ester (RE)-filled lipid droplets (LDs). Upon liver injury, HSCs adopt a myofibroblastic phenotype characterized by an elevated expression of extracellular matrix proteins and a concomitant loss of LDs. On the one hand, LD breakdown has been suggested to provide the energy required for HSC activation into myofibroblast-like cells. On the other hand, this process could mitigate HSC activation following the transformation of released REs into retinoic acids (RAs), ligands for nuclear receptors exerting antifibrotic transcriptional regulatory activities in HSCs. Importantly, RAs may also constitute a means for HSCs to orchestrate the liver response to injury by triggering transcriptional effects in multiple additional surrounding liver cell populations. We envision that new approaches, such as single-cell technologies, will allow to better define how RAs are issued from LD loss in HSCs exert a multicellular control of the liver (patho)physiology.
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Affiliation(s)
- Marie Bobowski-Gerard
- Institut Pasteur de Lille, The University of Lille, Inserm, CHU Lille, U1011-EGID, F-59000 Lille, France.
| | - Francesco Paolo Zummo
- Institut Pasteur de Lille, The University of Lille, Inserm, CHU Lille, U1011-EGID, F-59000 Lille, France.
| | - Bart Staels
- Institut Pasteur de Lille, The University of Lille, Inserm, CHU Lille, U1011-EGID, F-59000 Lille, France.
| | - Philippe Lefebvre
- Institut Pasteur de Lille, The University of Lille, Inserm, CHU Lille, U1011-EGID, F-59000 Lille, France.
| | - Jérôme Eeckhoute
- Institut Pasteur de Lille, The University of Lille, Inserm, CHU Lille, U1011-EGID, F-59000 Lille, France.
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42
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Martinez-Zubiaurre I, Chalmers AJ, Hellevik T. Radiation-Induced Transformation of Immunoregulatory Networks in the Tumor Stroma. Front Immunol 2018; 9:1679. [PMID: 30105016 PMCID: PMC6077256 DOI: 10.3389/fimmu.2018.01679] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2018] [Accepted: 07/09/2018] [Indexed: 12/27/2022] Open
Abstract
The implementation of novel cancer immunotherapies in the form of immune checkpoint blockers represents a major advancement in the treatment of cancer, and has renewed enthusiasm for identifying new ways to induce antitumor immune responses in patients. Despite the proven efficacy of neutralizing antibodies that target immune checkpoints in some refractory cancers, many patients do not experience therapeutic benefit, possibly owing to a lack of antitumor immune recognition, or to the presence of dominant immunosuppressive mechanisms in the tumor microenvironment (TME). Recent developments in this field have revealed that local radiotherapy (RT) can transform tumors into in situ vaccines, and may help to overcome some of the barriers to tumor-specific immune rejection. RT has the potential to ignite tumor immune recognition by generating immunogenic signals and releasing neoantigens, but the multiple immunosuppressive forces in the TME continue to represent important barriers to successful tumor rejection. In this article, we review the radiation-induced changes in the stromal compartments of tumors that could have an impact on tumor immune attack. Since different RT regimens are known to mediate strikingly different effects on the multifarious elements of the tumor stroma, special emphasis is given to different RT schedules, and the time after treatment at which the effects are measured. A better understanding of TME remodeling following specific RT regimens and the window of opportunity offered by RT will enable optimization of the design of novel treatment combinations.
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Affiliation(s)
- Inigo Martinez-Zubiaurre
- Department of Clinical Medicine, Faculty of Health Sciences, UiT the Arctic University of Norway, Tromsø, Norway
| | - Anthony J Chalmers
- Institute of Cancer Sciences, Beatson West of Scotland Cancer Centre, University of Glasgow, Glasgow, United Kingdom
| | - Turid Hellevik
- Department of Radiation Oncology, University Hospital of Northern Norway, Tromsø, Norway
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43
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Microvascular Mural Cell Organotypic Heterogeneity and Functional Plasticity. Trends Cell Biol 2018; 28:302-316. [DOI: 10.1016/j.tcb.2017.12.002] [Citation(s) in RCA: 96] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2017] [Revised: 12/12/2017] [Accepted: 12/13/2017] [Indexed: 01/28/2023]
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44
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Chen Y, Yousaf MN, Mehal WZ. Role of sterile inflammation in fatty liver diseases. LIVER RESEARCH 2018. [DOI: 10.1016/j.livres.2018.02.003] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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45
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Tedesco D, Grakoui A. Environmental peer pressure: CD4 + T cell help in tolerance and transplantation. Liver Transpl 2018; 24:89-97. [PMID: 28926189 PMCID: PMC5739992 DOI: 10.1002/lt.24873] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2017] [Revised: 06/30/2017] [Accepted: 09/12/2017] [Indexed: 12/20/2022]
Abstract
The liver participates in a multitude of metabolic functions that are critical for sustaining human life. Despite constant encounters with antigenic-rich intestinal blood, oxidative stress, and metabolic intermediates, there is no appreciable immune response. Interestingly, patients undergoing orthotopic liver transplantation benefit from a high rate of graft acceptance in comparison to other solid organ transplant recipients. In fact, cotransplantation of a donor liver in tandem with a rejection-prone graft increases the likelihood of graft acceptance. A variety of players may account for this phenomenon including the interaction of intrahepatic antigen-presenting cells with CD4+ T cells and the preferential induction of forkhead box P3 (Foxp3) expression on CD4+ T cells following injurious stimuli. Ineffective insult management can cause chronic liver disease, which manifests systemically as the following: antibody-mediated disorders, ineffective antiviral and antibacterial immunity, and gastrointestinal disorders. These sequelae sharing the requirement of CD4+ T cell help to coordinate aberrant immune responses. In this review, we will focus on CD4+ T cell help due to the shared requirements in hepatic tolerance and coordination of extrahepatic immune responses. Overall, intrahepatic deviations from steady state can have deleterious systemic immune outcomes and highlight the liver's remarkable capacity to maintain a balance between tolerance and inflammatory response while simultaneously being inundated with a panoply of antigenic stimuli. Liver Transplantation 24 89-97 2018 AASLD.
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Affiliation(s)
- Dana Tedesco
- Emory Vaccine Center, Division of Microbiology and Immunology, Emory University
| | - Arash Grakoui
- Emory Vaccine Center, Division of Microbiology and Immunology, Emory University,Division of Infectious Disease, Emory University School of Medicine, Atlanta, GA,Corresponding Author: Arash Grakoui, Division of Infectious diseases, Emory Vaccine Center, Division of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322, Telephone: (404) 727-9368;
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46
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Shang L, Hosseini M, Liu X, Kisseleva T, Brenner DA. Human hepatic stellate cell isolation and characterization. J Gastroenterol 2018; 53:6-17. [PMID: 29094206 DOI: 10.1007/s00535-017-1404-4] [Citation(s) in RCA: 96] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2017] [Accepted: 09/22/2017] [Indexed: 02/04/2023]
Abstract
The hepatic stellate cells (HSCs) localize at the space of Disse in the liver and have multiple functions. They are identified as the major contributor to hepatic fibrosis. Significant understanding of HSCs has been achieved using rodent models and isolated murine HSCs; as well as investigating human liver tissues and human HSCs. There is growing interest and need of translating rodent study findings to human HSCs and human liver diseases. However, species-related differences impose challenges on the translational research. In this review, we focus on the current information on human HSCs isolation methods, human HSCs markers, and established human HSC cell lines.
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Affiliation(s)
- Linshan Shang
- Department of Medicine, University of California, San Diego, La Jolla, USA
| | - Mojgan Hosseini
- Department of Pathology, University of California, San Diego, La Jolla, USA
| | - Xiao Liu
- Department of Surgery, University of California, San Diego, La Jolla, USA
| | - Tatiana Kisseleva
- Department of Surgery, University of California, San Diego, La Jolla, USA
| | - David Allen Brenner
- Department of Medicine, University of California, San Diego, La Jolla, USA.
- School of Medicine, UC San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0602, USA.
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47
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YILMAZ R, YUMUŞAK N, ATILGAN Hİ, KOCA G, KORKMAZ M. Radyoiodin (131I) Uygulanan Ratlarda Karaciğerdeki Histopatolojik Bulgular ve Hepatik Satellate Hücrelerde Artış. MEHMET AKIF ERSOY ÜNIVERSITESI VETERINER FAKÜLTESI DERGISI 2017. [DOI: 10.24880/maeuvfd.349014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
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48
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Castaño-Rodríguez N, Mitchell HM, Kaakoush NO. NAFLD, Helicobacter species and the intestinal microbiome. Best Pract Res Clin Gastroenterol 2017; 31:657-668. [PMID: 29566909 DOI: 10.1016/j.bpg.2017.09.008] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2017] [Accepted: 09/03/2017] [Indexed: 02/06/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease worldwide. It is well-accepted that gut dysbiosis is associated with NAFLD, however, there is some conflicting evidence regarding the nature of these alterations. Infection with Helicobacter species, mainly H. pylori, has also been associated with increased NAFLD risk, however, some studies have failed to reproduce this finding. Further studies including large study samples and standardised procedures for microbiota analyses, H. pylori detection and NAFLD diagnostic criteria, are required. The mechanisms involving Helicobacter species and the intestinal microbiome in NAFLD pathogenesis appear to be part of the multiple-hit theory, in which increased intestinal permeability, inflammatory responses, altered choline, bile acids and carbohydrate metabolism, production of short-chain fatty acids, urea cycle and urea transport systems, altered maintenance of hepatic γδT-17 cells, insulin resistance, hormones secreted by the adipose tissue, metabolic hormones, bacterial metabolites and Helicobacter toxins, are all implicated.
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Affiliation(s)
| | - Hazel M Mitchell
- School of Biotechnology and Biomolecular Sciences, UNSW Sydney, Sydney, NSW, 2052, Australia
| | - Nadeem O Kaakoush
- School of Medical Sciences, UNSW Sydney, Sydney, NSW, 2052, Australia
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49
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Larange A, Cheroutre H. Retinoic Acid and Retinoic Acid Receptors as Pleiotropic Modulators of the Immune System. Annu Rev Immunol 2017; 34:369-94. [PMID: 27168242 DOI: 10.1146/annurev-immunol-041015-055427] [Citation(s) in RCA: 168] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Vitamin A is a multifunctional vitamin implicated in a wide range of biological processes. Its control over the immune system and functions are perhaps the most pleiotropic not only for development but also for the functional fate of almost every cell involved in protective or regulatory adaptive or innate immunity. This is especially key at the intestinal border, where dietary vitamin A is first absorbed. Most effects of vitamin A are exerted by its metabolite, retinoic acid (RA), which through ligation of nuclear receptors controls transcriptional expression of RA target genes. In addition to this canonical function, RA and RA receptors (RARs), either as ligand-receptor or separately, play extranuclear, nongenomic roles that greatly expand the multiple mechanisms employed for their numerous and paradoxical functions that ultimately link environmental sensing with immune cell fate. This review discusses RA and RARs and their complex roles in innate and adaptive immunity.
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Affiliation(s)
- Alexandre Larange
- Division of Developmental Immunology, La Jolla Institute for Allergy & Immunology, La Jolla, California 92037; ,
| | - Hilde Cheroutre
- Division of Developmental Immunology, La Jolla Institute for Allergy & Immunology, La Jolla, California 92037; ,
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50
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Paquissi FC. Immunity and Fibrogenesis: The Role of Th17/IL-17 Axis in HBV and HCV-induced Chronic Hepatitis and Progression to Cirrhosis. Front Immunol 2017; 8:1195. [PMID: 29033929 PMCID: PMC5626935 DOI: 10.3389/fimmu.2017.01195] [Citation(s) in RCA: 64] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2017] [Accepted: 09/11/2017] [Indexed: 12/13/2022] Open
Abstract
Cirrhosis is a common final pathway for most chronic liver diseases; representing an increasing burden worldwide and is associated with increased morbidity and mortality. Current evidence has shown that, after an initial injury, the immune response has a significant participation in the ongoing damage, and progression from chronic viral hepatitis (CVH) to cirrhosis, driving the activation and maintenance of main fibrogenic pathways. Among immune deregulations, those related to the subtype 17 of T helper lymphocytes (Th17)/interleukin-17 (IL-17) axis have been recognized as key immunopathological and prognostic elements in patients with CVH. The Th17/IL-17 axis has been found involved in several points of fibrogenesis chain from the activation of stellate cells, increased expression of profibrotic factors as TGF-β, promotion of the myofibroblastic or epithelial–mesenchymal transition, stimulation of the synthesis of collagen, and induction of imbalance between matrix metalloproteinases and tissue inhibitors of metalloproteinases (TIMPs). It also promotes the recruitment of inflammatory cells and increases the expression of proinflammatory cytokines such as IL-6 and IL-23. So, the Th17/IL-17 axis is simultaneously the fuel and the flame of a sustained proinflammatory and profibrotic environment. This work aims to present the immunopathologic and prognostic role of the Th17/IL-17 axis and related pathways in fibrogenesis and progression to cirrhosis in patients with liver disease due to hepatitis B virus (HBV) and hepatitis C virus (HCV).
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