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Amajala KC, Gudivada IP, Malla RR. Gamma Delta T Cells: Role in Immunotherapy of Hepatocellular Carcinoma. Crit Rev Oncog 2023; 28:41-50. [PMID: 38050980 DOI: 10.1615/critrevoncog.2023049893] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/07/2023]
Abstract
The most typical type of liver cancer or hepatocellular carcinoma (HCC) develops from hepatocyte loss. Non-alcoholic fatty liver disease (NAFLD), viral hepatitis C and cirrhosis are the leading causes of HCC. With the Hepatitis B vaccine and medicines, there are several treatments for HCC, including liver resection, ablation, transplantation, immunotherapy, gene therapy, radiation embolization, and targeted therapy. Currently, a wide range of studies are carried out on gene therapy to identify biomarkers and pathways, which help us identify the exact stage of the disorder and reduce its effects. γδT cells have recently received much interest as a potential cancer treatment method in adaptive immunotherapy. γδT cells can quickly form connections between receptor and ligand activation. They can clonally expand and are a significant source of cytokines and chemokines. The present review provides a comprehensive understanding on the function of γδT cells in immunotherapies and how they are used to treat HCC.
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Affiliation(s)
- Krishna Chaitanya Amajala
- Department of Biochemistry and Bioinformatics, GITAM School of Science, GITAM Deemed to be University, Visakhapatnam 530045, Andhra Pradesh, India
| | - Indu Priya Gudivada
- Department of Biochemistry and Bioinformatics, GITAM School of Science, GITAM Deemed to be University, Visakhapatnam 530045, Andhra Pradesh, India
| | - Rama Rao Malla
- Cancer Biology Laboratory, Department of Biochemistry and Bioinformatics, School of Science, Gandhi Institute of Technology and Management (GITAM) (Deemed to be University), Visakhapatnam-530045, Andhra Pradesh, India; Department of Biochemistry and Bioinformatics, School of Science, GITAM (Deemed to be University), Visakhapatnam-530045, Andhra Pradesh, India
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Hu H, Liang L, Ge Q, Jiang X, Fu Z, Liu C, Long J. Correlation between Peripheral T Cell Subsets and the Activity of Thyroid-Associated Ophthalmopathy. Int J Endocrinol 2022; 2022:2705650. [PMID: 35311030 PMCID: PMC8924605 DOI: 10.1155/2022/2705650] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Accepted: 02/17/2022] [Indexed: 01/07/2023] Open
Abstract
INTRODUCTION Thyroid-associated ophthalmopathy (TAO) is the most common orbital immunological disease in adults. T cells play an important role in the pathogenesis of TAO. However, our knowledge of the circulating T cell subsets in TAO is limited. OBJECTIVE To investigate the circulating T cell subsets in TAO and the correlations between them and the activity of TAO. METHODS Thirty-eight TAO patients (19 active and 19 nonactive) were enrolled. The absolute number and percentage of total lymphocytes, CD3+T cells, CD4+T cells, CD8+ T cells, CD3+CD4-CD8-T cells (DNT cells), and CD3+CD4+CD8+ T cells (DPT cells) in peripheral blood were measured by flow cytometer. RESULTS TAO patients were divided into the active group and the nonactive group by the clinical activity score (CAS). The mean CAS was 4 ± 1.11 in the active group and 1.47 ± 0.61 in the nonactive group. No statistical differences were found in gender, age, and the levels of FT3, FT4, TSH, and TRAb between the two groups. The percentage of DNT cells was lower in the active group than in the non-active group, and it was negatively correlated with CAS (r = -0.349, P=0.032), but not the absolute number. The CD4/CD8 ratio, the absolute number and percentage of CD3+ T cells, CD4+ T cells, CD8+ T cells, and DPT cells did not differ between the two groups. CONCLUSION In the present study, we found the percentage of DNT cells was significantly lesser in the active TAO than in the nonactive TAO, and it was negatively correlated with the activity of the TAO. It suggests that DNT cells may involve in the immunopathogenesis of TAO and can serve as a clinical biomarker of the disease activity.
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Affiliation(s)
- Hong Hu
- Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Liang Liang
- Chongqing Key Laboratory of Ophthalmology, and Chongqing Eye Institute, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Qian Ge
- Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Xing Jiang
- Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Zhizheng Fu
- Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Chun Liu
- Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Jian Long
- Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
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Wu T, Hu J, Wang X, Luo X, Wang H, Ning Q. High-fat-induced nonalcoholic fatty liver potentiates vulnerability to and the severity of viral hepatitis in a C3H/HeN mouse model. Biofactors 2022; 48:216-227. [PMID: 34921696 DOI: 10.1002/biof.1811] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2021] [Accepted: 11/19/2021] [Indexed: 11/08/2022]
Abstract
Although the concomitance of nonalcoholic fatty liver disease (NAFLD) and viral hepatitis is soaring, there is not much knowledge about the impact of NAFLD on viral hepatitis. Here, we aimed to investigate how NAFLD influences the pathogenesis of viral hepatitis. Wild-type C3H/HeN mice with NAFLD induced by high-fat diet were infected with murine hepatitis virus 3 (MHV-3) and sacrificed at Days 4, 8, 12, and 16 post infection. Although there was no difference in the survival rate between mice with and without NAFLD, individuals with steatosis suffered more severe and prolonged liver injury demonstrated by transaminases and histology examination. The intrahepatic viral load was higher in NAFLD group during early infection, although it declined ultimately. On the contrary, the serum antiviral antibody titer remained in a lower level in mice with NAFLD throughout the investigation. In NAFLD group, the production of proinflammatory cytokines (tumor necrosis factor α, interleukin 1β, interleukin 6, and interleukin 17A) and the frequencies of antiviral immune cells (NKG2D+ NK cells and CD69+ cytotoxic T lymphocytes [CTLs]) were profoundly increased. Parallelly, the production of anti-inflammatory cytokine (interleukin 10) and inhibitory checkpoint expression (NKG2A on NK cells and programmed cell death-1 on CTLs) were also significantly elevated to maintain homeostasis. However, the upregulation of interleukin 22, a protective cytokine was deficient in NAFLD group post MHV-3 infection. Conclusively, hepatic lipid metabolic abnormalities disturb antiviral immunity and increase the vulnerability to and severity of viral hepatitis.
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Affiliation(s)
- Ting Wu
- Institute and Department of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Junjian Hu
- Institute and Department of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Xiaojing Wang
- Institute and Department of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Xiaoping Luo
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Hongwu Wang
- Institute and Department of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Qin Ning
- Institute and Department of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
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Cross-talk between hepatic stellate cells and T lymphocytes in liver fibrosis. Hepatobiliary Pancreat Dis Int 2021; 20:207-214. [PMID: 33972160 DOI: 10.1016/j.hbpd.2021.04.007] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Accepted: 04/21/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND Fibrosis results from inflammation and healing following injury. The imbalance between extracellular matrix (ECM) secretion and degradation leads to the ECM accumulation and liver fibrosis. This process is regulated by immune cells. T lymphocytes, including alpha beta (αβ) T cells, which have adaptive immune functions, and gamma delta (γδ) T cells, which have innate immune functions, are considered regulators of liver fibrosis. This review aimed to present the current understanding of the cross-talk between T lymphocytes and hepatic stellate cells (HSCs), which are the key cells in liver fibrosis. DATA SOURCES The keywords "liver fibrosis", "immune", and "T cells" were used to retrieve articles published in PubMed database before January 31, 2020. RESULTS The ratio of CD8+ (suppressor) T cells to CD4+ (helper) T cells is significantly higher in the liver than in the peripheral blood. T cells secrete a series of cytokines and chemokines to regulate the inflammation in the liver and the activation of HSCs to influence the course of liver fibrosis. In addition, HSCs also regulate the differentiation and proliferation of T cells. CONCLUSIONS The cross-talk between T cells and HSCs regulates liver fibrosis progression. The elucidation of this communication process will help us to understand the pathological process of liver fibrosis.
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Zhou QH, Wu FT, Pang LT, Zhang TB, Chen Z. Role of γδT cells in liver diseases and its relationship with intestinal microbiota. World J Gastroenterol 2020; 26:2559-2569. [PMID: 32523311 PMCID: PMC7265152 DOI: 10.3748/wjg.v26.i20.2559] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2020] [Revised: 04/19/2020] [Accepted: 04/28/2020] [Indexed: 02/06/2023] Open
Abstract
γδT cells are unconventional T lymphocytes that bridge innate and adaptive immunity. Based on the composition of T cell receptor and the cytokines produced, γδT cells can be divided into diverse subsets that may be present at different locations, including the liver, epithelial layer of the gut, the dermis and so on. Many of these cells perform specific functions in liver diseases, such as viral hepatitis, autoimmune liver diseases, non-alcoholic fatty liver disease, liver cirrhosis and liver cancers. In this review, we discuss the distribution, subsets, functions of γδT cells and the relationship between the microbiota and γδT cells in common hepatic diseases. As γδT cells have been used to cure hematological and solid tumors, we are interested in γδT cell-based immunotherapies to treat liver diseases.
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Affiliation(s)
- Qi-Hui Zhou
- Department of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310000, Zhejiang Province, China
| | - Feng-Tian Wu
- Department of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310000, Zhejiang Province, China
| | - Lan-Tian Pang
- Department of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310000, Zhejiang Province, China
| | - Tian-Bao Zhang
- Department of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310000, Zhejiang Province, China
| | - Zhi Chen
- Department of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310000, Zhejiang Province, China
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Shi X, Yu L, Zhang Y, Liu Z, Zhang H, Zhang Y, Liu P, Du P. Glycyrrhetinic acid alleviates hepatic inflammation injury in viral hepatitis disease via a HMGB1-TLR4 signaling pathway. Int Immunopharmacol 2020; 84:106578. [PMID: 32416454 PMCID: PMC7205693 DOI: 10.1016/j.intimp.2020.106578] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2019] [Revised: 04/24/2020] [Accepted: 05/06/2020] [Indexed: 12/24/2022]
Abstract
Licorice defect in TCM recipes leads to the hepatotoxicity in administrated mice. GA inhibits viral hepatitis by suppressing HMGB1 release and cytokine activity. GA treatment effect on infected mice is similar with HMGB1 neutralizing antibody. HMGB1-TLR4 axis is involved in murine hepatic injury during MHV infection. Various human disorders are cured by the use of licorice, a key ingredient of herbal remedies. Glycyrrhizic acid (GL), a triterpenoid glycoside, is the aqueous extract from licorice root. Glycyrrhetinic acid (GA) has been reported to be a major bioactive hydrolysis product of GL and has been regarded as an anti-inflammatory agent for the treatment of a variety of inflammatory diseases, including hepatitis. However, the mechanism by which GA inhibits viral hepatic inflammatory injury is not completely understood. In this study, we found that, by consecutively treating mice with a traditional herbal recipe, licorice plays an important role in the detoxification of mice. We also employed a murine hepatitis virus (MHV) infection model to illustrate that GA treatment inhibited activation of hepatic inflammatory responses by blocking high-mobility group box 1 (HMGB1) cytokine activity. Furthermore, decreased HMGB1 levels and downstream signaling triggered by injection of a neutralizing HMGB1 antibody or TLR4 gene deficiency, also significantly protected against MHV-induced severe hepatic injury. Thus, our findings characterize GA as a hepatoprotective therapy agent in hepatic infectious disease not only by suppressing HMGB1 release and blocking HMGB1 cytokine activity, but also via an underlying viral-induced HMGB1-TLR4 immunological regulation axis that occurs during the cytokine storm. The present study provides a new therapy strategy for the treatment of acute viral hepatitis in the clinical setting.
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MESH Headings
- Animals
- Anti-Inflammatory Agents/pharmacology
- Anti-Inflammatory Agents/therapeutic use
- Cell Line
- Cytokines/genetics
- Drugs, Chinese Herbal/pharmacology
- Drugs, Chinese Herbal/therapeutic use
- Female
- Glycyrrhetinic Acid/pharmacology
- Glycyrrhetinic Acid/therapeutic use
- Glycyrrhiza
- HMGB1 Protein/immunology
- Hepatitis, Viral, Animal/drug therapy
- Hepatitis, Viral, Animal/genetics
- Hepatitis, Viral, Animal/immunology
- Liver/drug effects
- Liver/immunology
- Mice, Inbred C57BL
- Mice, Knockout
- Murine hepatitis virus
- Signal Transduction/drug effects
- Toll-Like Receptor 4/genetics
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Affiliation(s)
- Xiaodong Shi
- National Center for Occupational Safety and Health, National Health Commission of the People's Republic of China, Beijing 102308, China.
| | - Lijia Yu
- National Center for Occupational Safety and Health, National Health Commission of the People's Republic of China, Beijing 102308, China
| | - Yinglin Zhang
- National Center for Occupational Safety and Health, National Health Commission of the People's Republic of China, Beijing 102308, China
| | - Zequan Liu
- National Center for Occupational Safety and Health, National Health Commission of the People's Republic of China, Beijing 102308, China
| | - Huawei Zhang
- National Center for Occupational Safety and Health, National Health Commission of the People's Republic of China, Beijing 102308, China
| | - Yansong Zhang
- National Center for Occupational Safety and Health, National Health Commission of the People's Republic of China, Beijing 102308, China
| | - Ping Liu
- CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
| | - Peishuang Du
- CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
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Lu Y, Lin Y, Huang X, Wu S, Wei J, Yang C. Oxaliplatin aggravates hepatic oxidative stress, inflammation and fibrosis in a non‑alcoholic fatty liver disease mouse model. Int J Mol Med 2019; 43:2398-2408. [PMID: 30942432 PMCID: PMC6488186 DOI: 10.3892/ijmm.2019.4154] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2018] [Accepted: 03/27/2019] [Indexed: 02/06/2023] Open
Abstract
Oxaliplatin (OXA)-based chemotherapy is widely used in the treatment of gastrointestinal tumors; however, it is associated with chemotherapy-associated liver injury. Whether OXA induces liver injury and aggravates the already existing hepatic oxidative stress, inflammation and fibrosis in non-alcoholic fatty liver disease (NAFLD), and whether these effects can be alleviated by reduced glutathione (GSH) treatment, remains unclear. In the present study, OXA induced acute liver injury in NAFLD mice. Moreover, OXA increased the levels of reactive oxygen species (ROS) and malondialdehyde (MDA) and decreased the levels of superoxide dismutase and GSH peroxidase in the livers of NAFLD mice. OXA also induced the upregulation of hepatic inflammatory cytokines, such as tumor necrosis factor (TNF)-α, interferon (IFN)-γ and interleukin (IL)-17, in NAFLD mice. Furthermore, collagen fiber deposition in liver tissues was increased and the expression of transforming growth factor (TGF)-β, α-smooth muscle actin (SMA) and tissue inhibitor of metallopeptidase (TIMP)-1 was upregulated in the livers of OXA-treated NAFLD mice. Treatment with exogenous GSH alleviated OXA-induced acute liver injury in NAFLD mice, and significantly reduced the levels of ROS, MDA and TNF-α. However, GSH treatment did not inhibit collagen fiber deposition, although it reduced the levels of IFN-γ, IL-17, TGF-β, α-SMA and TIMP-1 in the livers of OXA-treated NAFLD mice. In conclusion, OXA chemotherapy may induce acute liver injury and aggravate the existing hepatic oxidative stress, inflammation and fibrosis in NAFLD. Treatment of NAFLD mice with exogenous GSH alleviated OXA-induced liver injury, possibly by ameliorating OXA-aggravated hepatic oxidative stress and inflammation; it did not, however, attenuate OXA-aggravated liver fibrosis.
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Affiliation(s)
- Yulei Lu
- Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Youzhi Lin
- Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Xiaoqing Huang
- Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Shengming Wu
- Department of Pathology, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Jian Wei
- Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Chun Yang
- Department of Experimental Pathology, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
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Abstract
CD3+CD4-CD8- T cells (double-negative T cells; DNTs) have diverse functions in peripheral immune-related diseases by regulating immunological and inflammatory homeostasis. However, the functions of DNTs in the central nervous system remain unknown. Here, we found that the levels of DNTs were dramatically increased in both the brain and peripheral blood of stroke patients and in a mouse model in a time-dependent manner. The infiltrating DNTs enhanced cerebral immune and inflammatory responses and exacerbated ischemic brain injury by modulating the FasL/PTPN2/TNF-α signaling pathway. Blockade of this pathway limited DNT-mediated neuroinflammation and improved the outcomes of stroke. Our results identified a critical function of DNTs in the ischemic brain, suggesting that this unique population serves as an attractive target for the treatment of ischemic stroke.
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Yu H, Liu Y, Wang H, Wan X, Huang J, Yan W, Xi D, Luo X, Shen G, Ning Q. Clara Cell 10 kDa Protein Alleviates Murine Hepatitis Virus Strain 3-Induced Fulminant Hepatitis by Inhibiting Fibrinogen-Like Protein 2 Expression. Front Immunol 2018; 9:2935. [PMID: 30619295 PMCID: PMC6300492 DOI: 10.3389/fimmu.2018.02935] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2018] [Accepted: 11/29/2018] [Indexed: 12/22/2022] Open
Abstract
Background: Fulminant hepatitis (FH) is a serious threat to human life, accompanied by massive and rapid necroinflammation. Kupffer cells, the major immune cell population involved in innate immune responses, are considered to be central for FH. Fibrinogen-like protein 2 (Fgl2) is a pro-coagulant protein that is substantially induced in macrophages upon viral infection, and Fgl2 depletion represses murine hepatitis virus strain 3 (MHV-3) infection. Clara cell 10 kDa (CC10) protein is a secretory protein with anti-inflammatory properties in allergic rhinitis and asthma. However, its mechanisms of action and pathogenic roles in other disease are still unclear. In this study, we aimed to determine the role of CC10 in FH and the regulation of Fgl2 by CC10. Methods: A mouse FH model was established by peritoneal injection of MHV-3. The mice received CC10 protein through tail vein injection before viral infection. Survival rate, liver function, liver histology, fibrin deposition, and necrosis were examined. The regulatory effect of CC10 on Fgl2 expression was investigated using THP-1 cells and mouse peritoneal macrophages in vitro. Results: In the mouse FH model induced by MHV-3, the survival rate increased from 0 to 12.5% in the CC10 group compared to that in the saline-only control group. Meanwhile, the levels of ALT and AST in serum were significantly decreased and liver damage was reduced. Furthermore, hepatic Fgl2, TNF-α, and IL-1β expression was obviously downregulated together with fibrin deposition, and hepatocyte apoptosis was reduced after administration of CC10 protein. In vitro, CC10 was found to significantly inhibit the expression of Fgl2 in IFN-γ-treated THP-1 cells and MHV-3-infected mouse peritoneal macrophages by western blot and real-time PCR. However, there was no direct interaction between CC10 and Fgl2 as shown by co-immunoprecipitation. Microarray investigations suggested that HMG-box transcription factor 1 (HBP1) was significantly low in CC10-treated and IFN-γ-primed THP-1 cells. HBP1-siRNA treatment abrogated the inhibitory effect of CC10 on Fgl2 expression in Human Umbilical Vein Endothelial cells (HUVECs). Conclusion:CC10 protects against MHV-3-induced FH via suppression of Fgl2 expression in macrophages. Such effects may be mediated by the transcription factor HBP1.
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MESH Headings
- Animals
- CHO Cells
- Coronavirus Infections/immunology
- Coronavirus Infections/mortality
- Coronavirus Infections/pathology
- Coronavirus Infections/virology
- Cricetulus
- Disease Models, Animal
- Female
- Fibrinogen/genetics
- Fibrinogen/metabolism
- Hepatitis, Viral, Animal/immunology
- Hepatitis, Viral, Animal/mortality
- Hepatitis, Viral, Animal/pathology
- Hepatitis, Viral, Animal/virology
- High Mobility Group Proteins/metabolism
- Human Umbilical Vein Endothelial Cells
- Humans
- Liver/immunology
- Liver/pathology
- Liver/virology
- Liver Failure, Acute/immunology
- Liver Failure, Acute/mortality
- Liver Failure, Acute/pathology
- Liver Failure, Acute/virology
- Macrophages/immunology
- Macrophages/metabolism
- Mice
- Mice, Inbred BALB C
- Murine hepatitis virus/immunology
- Murine hepatitis virus/pathogenicity
- Necrosis/immunology
- Necrosis/pathology
- Necrosis/virology
- Recombinant Proteins/genetics
- Recombinant Proteins/metabolism
- Repressor Proteins/metabolism
- Survival Rate
- THP-1 Cells
- Uteroglobin/genetics
- Uteroglobin/metabolism
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Affiliation(s)
- Haijing Yu
- Department of Infectious Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yang Liu
- Department of Otolaryngology-Head and Neck Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hongwu Wang
- Department of Infectious Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaoyang Wan
- Department of Infectious Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jiaquan Huang
- Department of Infectious Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Weiming Yan
- Department of Infectious Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Dong Xi
- Department of Infectious Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaoping Luo
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Guanxin Shen
- Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qin Ning
- Department of Infectious Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Yu H, Liu Y, Huang J, Wang H, Yan W, Xi D, Shen G, Luo X, Ning Q. IL-33 protects murine viral fulminant hepatitis by targeting coagulation hallmark protein FGL2/fibroleukin expression. Mol Immunol 2017; 87:171-179. [PMID: 28494352 DOI: 10.1016/j.molimm.2017.04.011] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2016] [Revised: 04/21/2017] [Accepted: 04/22/2017] [Indexed: 12/13/2022]
Abstract
Fulminant hepatitis (FH) is characterized by rapid liver failure and high mortality. The pathogenesis of viral FH includes virus-induced immune activation, inflammation, and subsequent hepatic apoptosis and necrosis. However, the mechanisms that underlie FH progression are unclear. IL-33 is a member of the IL-1-related cytokines, considered to be an "alarmin" that participates in various diseases, but its precise role in the coagulation of FH is not very clear. In our study, we found that IL-33 is significantly elevated in mice infected with murine hepatitis virus strain 3 (MHV-3). This is accompanied by an increase in pro-coagulant fibrinogen-like protein 2 (FGL2) in the liver. Previous studies have suggested that an increase in FGL2 is diagnostic of FH and liver necrosis, and animals with no FGL2 had better survivorship during FH. Our studies showed that IL-33 administration in a MHV-3 infection promoted survival during FH, with a significant reduction in FGL2 expression and liver inflammation. In vitro IL-33 treatment abrogated MHV-3 and IFN-γ induced FGL2 expression in RAW264.7 and THP-1 cells, respectively. In conclusion, our research suggests that IL-33 protects against viral fulminant hepatitis in mice by antagonizing expression of the pro-coagulant protein FGL2.
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Affiliation(s)
- Haijing Yu
- Department of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yang Liu
- Department of Otolaryngology-Head and Neck Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jiaquan Huang
- Department of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hongwu Wang
- Department of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Weiming Yan
- Department of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Dong Xi
- Department of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Guanxin Shen
- Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaoping Luo
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qin Ning
- Department of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
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Liang Y, Kwota Z, Sun J. Intrahepatic regulation of antiviral T cell responses at initial stages of viral infection. Int Immunopharmacol 2016; 39:106-112. [PMID: 27459170 DOI: 10.1016/j.intimp.2016.07.021] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2016] [Revised: 07/19/2016] [Accepted: 07/19/2016] [Indexed: 12/17/2022]
Abstract
It is generally accepted that the appropriate boost of early immune response will control viral replications and limit the immune-mediated pathology in viral hepatitis. However, poor immunity results in viral persistence, chronic inflammation and finally liver cirrhosis and carcinoma. As a peripheral non-lymphoid organ of immune surveillance, the liver continually encounters hundreds of molecules from the blood, including nutrients, toxins and pathogens. In this way, the liver maintains immune tolerance under healthy conditions, but responds quickly to the hepatotropic pathogens during the early stages of an infection. Although our knowledge of liver cell compositions and functions has been improved significantly in recent years, the intrahepatic immune regulation of antiviral T cells at the initial stage is complex and not well elucidated. Here, we summarize the role of liver cell subpopulations in regulating antiviral T cell response at the initial stages of viral infection. A better understanding of early hepatic immune regulation will pave the way for the development of novel therapies and vaccine design for human viral hepatitis.
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Affiliation(s)
- Yuejin Liang
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555-1070, USA.
| | - Zakari Kwota
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555-1070, USA
| | - Jiaren Sun
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555-1070, USA
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12
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Adaptive immunity in the liver. Cell Mol Immunol 2016; 13:354-68. [PMID: 26996069 PMCID: PMC4856810 DOI: 10.1038/cmi.2016.4] [Citation(s) in RCA: 73] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2015] [Revised: 01/06/2016] [Accepted: 01/09/2016] [Indexed: 02/06/2023] Open
Abstract
The anatomical architecture of the human liver and the diversity of its immune components endow the liver with its physiological function of immune competence. Adaptive immunity is a major arm of the immune system that is organized in a highly specialized and systematic manner, thus providing long-lasting protection with immunological memory. Adaptive immunity consists of humoral immunity and cellular immunity. Cellular immunity is known to have a crucial role in controlling infection, cancer and autoimmune disorders in the liver. In this article, we will focus on hepatic virus infections, hepatocellular carcinoma and autoimmune disorders as examples to illustrate the current understanding of the contribution of T cells to cellular immunity in these maladies. Cellular immune suppression is primarily responsible for chronic viral infections and cancer. However, an uncontrolled auto-reactive immune response accounts for autoimmunity. Consequently, these immune abnormalities are ascribed to the quantitative and functional changes in adaptive immune cells and their subsets, innate immunocytes, chemokines, cytokines and various surface receptors on immune cells. A greater understanding of the complex orchestration of the hepatic adaptive immune regulators during homeostasis and immune competence are much needed to identify relevant targets for clinical intervention to treat immunological disorders in the liver.
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Doherty DG. Immunity, tolerance and autoimmunity in the liver: A comprehensive review. J Autoimmun 2015; 66:60-75. [PMID: 26358406 DOI: 10.1016/j.jaut.2015.08.020] [Citation(s) in RCA: 226] [Impact Index Per Article: 22.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2015] [Accepted: 08/26/2015] [Indexed: 12/14/2022]
Abstract
The hepatic immune system is constantly exposed to a massive load of harmless dietary and commensal antigens, to which it must remain tolerant. Immune tolerance in the liver is mediated by a number of specialized antigen-presenting cells, including dendritic cells, Kupffer cells, liver sinusoidal endothelial cells and hepatic stellate cells. These cells are capable of presenting antigens to T cells leading to T cell apoptosis, anergy, or differentiation into regulatory T cells. However, the hepatic immune system must also be able to respond to pathogens and tumours and therefore must be equipped with mechanisms to override immune tolerance. The liver is a site of accumulation of a number of innate lymphocyte populations, including natural killer cells, CD56(+) T cells, natural killer T cells, γδ T cells, and mucosal-associated invariant T cells. Innate lymphocytes recognize conserved metabolites derived from microorganisms and host cells and respond by killing target cells or promoting the differentiation and/or activation of other cells of the immune system. Innate lymphocytes can promote the maturation of antigen-presenting cells from their precursors and thereby contribute to the generation of immunogenic T cell responses. These cells may be responsible for overriding hepatic immune tolerance to autoantigens, resulting in the induction and maintenance of autoreactive T cells that mediate liver injury causing autoimmune liver disease. Some innate lymphocyte populations can also directly mediate liver injury by killing hepatocytes or bile duct cells in murine models of hepatitis, whilst other populations may protect against liver disease. It is likely that innate lymphocyte populations can promote or protect against autoimmune liver disease in humans and that these cells can be targeted therapeutically. Here I review the cellular mechanisms by which hepatic antigen-presenting cells and innate lymphocytes control the balance between immunity, tolerance and autoimmunity in the liver.
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Affiliation(s)
- Derek G Doherty
- Division of Immunology, School of Medicine, Trinity College Dublin, Ireland.
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Liu J, Tan Y, Zhang J, Zou L, Deng G, Xu X, Wang F, Ma Z, Zhang J, Zhao T, Liu Y, Li Y, Zhu B, Guo B. C5aR, TNF-α, and FGL2 contribute to coagulation and complement activation in virus-induced fulminant hepatitis. J Hepatol 2015; 62:354-62. [PMID: 25200905 DOI: 10.1016/j.jhep.2014.08.050] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2014] [Revised: 08/29/2014] [Accepted: 08/31/2014] [Indexed: 12/04/2022]
Abstract
BACKGROUND & AIMS Viral fulminant hepatitis (FH) is a disease with a high mortality rate. Activation of the complement system correlates with the development of FH. However, the key factors mediating complement activation in FH remain elusive. METHODS Liver tissues were isolated from FH patients infected by hepatitis B virus (HBV) and from mice infected with murine hepatitis virus strain 3 (MHV-3). Wild type mice were treated with or without antagonists of C5aR or TNF-α, and mice deficient for C5aR (C5aR(-/-)), Fgl2 (Fgl2(-/-)), and Tnfα (Tnfα(-/-)) mice were not treated with the antagonists. C5b-9, C5aR, FGL2, CD31, CD11b, fibrin, TNF-α, and complement C3 cleavage products were detected by immunohistochemistry, immunofluorescence, or ELISA. Sorted liver sinusoidal endothelial cells (LSECs) or myeloid-derived (CD11b(+)) cells were stimulated with C5a, TNF-α or MHV-3 in vitro. The mRNA expressions levels of Fgl2 and Tnfα were determined by qRT-PCR analyses. RESULTS We observed that complement activation, coagulation and pro-inflammatory cytokine production were upregulated in the HBV(+) patients with FH. Similar observations were made in the murine FH models. Complement activation and coagulation were significantly reduced in MHV-3 infected mice in the absence of C5aR, Tnfα or Fgl2. The MHV-3 infected C5aR(-/-) mice exhibited reduced numbers of infiltrated inflammatory CD11b(+) cells and a reduced expression of TNF-α and FGL2. Moreover, C5a administration stimulated TNF-α production by CD11b(+) cells, which in turn promoted the expression of FGL2 in CD31(+) LSEC-like cells in vitro. Administration of antagonists against C5aR or TNF-α ameliorated MHV-3-induced FH. CONCLUSIONS Our results demonstrate that C5aR, TNF-α, and FGL2 form an integral network that contributes to coagulation and complement activation, and suggest that those are potential therapeutic targets in viral FH intervention.
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Affiliation(s)
- Jianjun Liu
- Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing, China; Department of Histology & Embryology, Third Military Medical University, Chongqing, China
| | - Yulong Tan
- Department of Immunology, Third Military Medical University, Chongqing, China
| | - Jinyu Zhang
- Department of Immunology, Third Military Medical University, Chongqing, China
| | - Liyun Zou
- Department of Immunology, Third Military Medical University, Chongqing, China
| | - Guohong Deng
- Institute of Infectious Diseases, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Xueqing Xu
- Department of Medical Genetics, Third Military Medical University, Chongqing, China
| | - Feng Wang
- Department of Laboratory Medicine, Daping Hospital, Third Military Medical University, Chongqing, China
| | - Zhengwei Ma
- Institute of Hepatobiliary Surgery & Southwest Hospital, Third Military Medical University, District Shapingba, Chongqing, China
| | - Jue Zhang
- Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Tingting Zhao
- Department of Immunology, Third Military Medical University, Chongqing, China
| | - Yunlai Liu
- Department of Histology & Embryology, Third Military Medical University, Chongqing, China
| | - Yongsheng Li
- Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Bo Zhu
- Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing, China.
| | - Bo Guo
- Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing, China; Department of Immunology, Third Military Medical University, Chongqing, China.
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Hammerich L, Tacke F. Role of gamma-delta T cells in liver inflammation and fibrosis. World J Gastrointest Pathophysiol 2014; 5:107-113. [PMID: 24891982 PMCID: PMC4025070 DOI: 10.4291/wjgp.v5.i2.107] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2013] [Revised: 01/24/2014] [Accepted: 03/17/2014] [Indexed: 02/06/2023] Open
Abstract
Conventional adaptive T cell responses contribute to liver inflammation and fibrogenesis, especially in chronic viral infections and autoimmune hepatitis. However, the role of unconventional gamma-delta (γδ) T cells in liver diseases is less clear. In the past two decades, accumulating evidence revealed that γδ T cell numbers remarkably increase in the liver upon various inflammatory conditions in mice and humans. More recent studies demonstrated that the functional effect of γδ T cells on liver disease progression depends on the subsets involved, which can be identified by the expression of distinct T cell receptor chains and of specific cytokines. Fascinatingly, γδ T cells may have protective as well as pathogenic functions in liver diseases. Interferon γ-producing γδ T cells, for example, induce apoptosis in hepatocytes but also in hepatic tumor cells; while interleukin-17-expressing γδ T cells can downregulate pathogenic effector functions of other immune cells and can promote apoptosis of fibrogenic stellate cells. However, the results obtained in human liver disease as well as murine models are not fully conclusive at present, and the effects of γδ T cells on the outcome of liver disease might vary dependent on etiology and stage of disease. Further definitions of the γδ T cell subsets involved in acute and chronic liver inflammation, as well as their effector cytokines might uncover whether interference with γδ T cells could be a useful target for the treatment of liver disease.
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Cohen CA, Shea AA, Heffron CL, Schmelz EM, Roberts PC. The parity-associated microenvironmental niche in the omental fat band is refractory to ovarian cancer metastasis. Cancer Prev Res (Phila) 2013; 6:1182-93. [PMID: 24022590 DOI: 10.1158/1940-6207.capr-13-0227] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Ovarian cancer is an insidious and aggressive disease of older women, typically undiscovered before peritoneal metastasis due to its asymptomatic nature and lack of early detection tools. Epidemiologic studies suggest that child-bearing (parity) is associated with decreased ovarian cancer risk, although the molecular mechanisms responsible for this phenomenon have not been delineated. Ovarian cancer preferentially metastasizes to the omental fat band (OFB), a secondary lymphoid organ that aids in filtration of the peritoneal serous fluid (PSF) and helps combat peritoneal infections. In the present study, we assessed how parity and age impact the immune compositional profile in the OFB of mice, both in the homeostatic state and as a consequence of peritoneal implantation of ovarian cancer. Using fluorescence-activated cell sorting analysis and quantitative real-time PCR, we found that parity was associated with a significant reduction in omental monocytic subsets and B1-B lymphocytes, correlating with reduced homeostatic expression levels of key chemoattractants and polarization factors (Ccl1, Ccl2, Arg1, and Cxcl13). Of note, parous animals exhibited significantly reduced tumor burden following intraperitoneal implantation compared with nulliparous animals. This was associated with a reduction in tumor-associated neutrophils and macrophages, as well as in the expression levels of their chemoattractants (Cxcl1 and Cxcl5) in the OFB and PSF. These findings define a preexisting "parity-associated microenvironmental niche" in the OFB that is refractory to metastatic tumor seeding and outgrowth. Future studies designed to manipulate this niche may provide a novel means to mitigate peritoneal dissemination of ovarian cancer.
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Affiliation(s)
- Courtney A Cohen
- Virginia Polytechnic Institute and State University, Integrated Life Sciences Building, 1981 Kraft Drive (0913), Blacksburg, VA 24061. ; and Eva M. Schmelz,
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