|
1
|
Lei M, Chen G. Integration of mechanics and immunology: Perspective for understanding fibrotic disease mechanisms and innovating therapeutic strategies. Acta Biomater 2025:S1742-7061(25)00333-2. [PMID: 40324516 DOI: 10.1016/j.actbio.2025.05.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2025] [Revised: 05/01/2025] [Accepted: 05/02/2025] [Indexed: 05/07/2025]
Abstract
The treatment of fibrotic diseases has long posed a medical challenge due to the complex mechanisms underlying their occurrence and progression. Emerging evidence suggests that fibrosis development is influenced not only by biochemical factors but also by the activation of mechanotransduction in response to mechanical stimuli. Mechanoimmunology, an interdisciplinary field that examines how the immune system is influenced by physical forces and mechanical environments, has recently demonstrated significant importance and considerable potential for application in the study of fibrotic diseases. While the mechanisms by which biochemical signals regulate the immune system have been extensively explored, the progression of fibrosis is often impacted by both immune dysregulation and mechanical changes. During fibrosis, immune cells encounter strong mechanical stimuli, such as stiffer substrates and altered viscoelasticity, which activate their own mechanotransduction pathways and subsequently influence fibrosis progression. Targeting the mechanosensation of immune cells to enhance or inhibit their mechanoreception and mechanotransduction, thereby enhancing the anti-fibrotic role they play in the fibrotic process, could help innovate therapeutic strategies for fibrotic diseases. STATEMENT OF SIGNIFICANCE: Fibrotic disease progression is often associated with dysregulation of both tissue mechanical properties and immune responses. The fibrotic microenvironment's altered mechanical properties both result from and drive fibrosis, while immune cells actively sense and respond to these mechanical cues through mechanotransduction pathways. Emerging mechanoimmunology research highlights how mechanical stimuli influence immune cell behavior, yet the precise regulatory mechanisms remain unclear. This review examines mechanical communication in fibrosis, focusing on immune cells' mechanosensing capabilities and their role in disease progression, which helps to enhance our understanding of the pathogenesis of fibrosis and inform innovative strategies to open up mechano-immune pathways targeting fibrosis therapy.
Collapse
Affiliation(s)
- Min Lei
- School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing 400054, PR China
| | - Guobao Chen
- School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing 400054, PR China.
| |
Collapse
|
|
2
|
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.
Collapse
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
| |
Collapse
|
|
3
|
Zhang S, Mak LY, Yuen MF, Seto WK. Mechanisms of hepatocellular carcinoma and cirrhosis development in concurrent steatotic liver disease and chronic hepatitis B. Clin Mol Hepatol 2025; 31:S182-S195. [PMID: 39568126 PMCID: PMC11925439 DOI: 10.3350/cmh.2024.0837] [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: 09/25/2024] [Revised: 11/13/2024] [Accepted: 11/16/2024] [Indexed: 11/22/2024] Open
Abstract
Chronic hepatitis B (CHB) poses a major global public health challenge and is a leading cause of cirrhosis and liver cancer. Hepatic steatosis is common in individuals with CHB compared to the non-CHB population and is particularly prevalent in hepatitis B virus (HBV)-endemic regions, affecting about one-third of CHB patients. The interaction between hepatic steatosis and CHB-related disease progression is complex and still under debate. Evidence demonstrates that co-existing steatosis may worsen liver fibrosis while paradoxically increasing the likelihood of achieving better HBV control. In particular, despite the association of steatotic liver disease (SLD) with lower HBV viral loads and higher rates of HBsAg seroclearance, the coexistence of CHB and SLD can potentially accelerate liver disease progression. Factors such as fat deposition, lipotoxicity, oxidative stress, and chronic inflammation in SLD may foster a pro-fibrotic and pro-carcinogenic environment, accelerating the disease progression. Additionally, loss of global DNA methylation, changes in the immune microenvironment, and genetic susceptibility further contribute to the development of CHB-related cirrhosis and hepatocellular carcinoma (HCC). This review examines the mechanisms driving liver disease progression and the heightened risk of cirrhosis and HCC in patients with concurrent CHB and steatotic liver disease, underscoring the importance of prioritizing antiviral therapy for CHB in addition to addressing SLD.
Collapse
Affiliation(s)
- Saisai Zhang
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong
| | - Lung-Yi Mak
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
| | - Man-Fung Yuen
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
| | - Wai-Kay Seto
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
- Department of Medicine, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
| |
Collapse
|
|
4
|
Li X, Gu Y, Liao C, Ma X, Bi Y, Lian Y, Huang Y. A comprehensive model to better screen out antiviral treatment candidates for chronic hepatitis B patients. Int Immunopharmacol 2024; 140:112848. [PMID: 39096876 DOI: 10.1016/j.intimp.2024.112848] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2024] [Revised: 04/03/2024] [Accepted: 07/29/2024] [Indexed: 08/05/2024]
Abstract
BACKGROUND Chronic hepatitis B virus (HBV) infection is a serious human health threat given its high morbidity and mortality. Timely and effective antiviral treatment can postpone liver disease progression and reduce the occurrence of HBV-related end-stage liver disease. At present, the antiviral treatment criteria are mainly based on alanine transaminase (ALT) levels, HBV DNA levels and HBV e antigen levels according to the American Association for the Study of Liver Diseases treatment guidelines. However, some chronic hepatitis B (CHB) patients not meeting the above criteria still experience liver disease progression without antiviral treatment. It is urgent to identify a more comprehensive tool to screen out more antiviral treatment candidates as soon as possible. METHODS Considering the vital role of the immune response in the development of HBV infection and CHB cure, we collected data from 335 treatment-naïve CHB patients and comprehensively analysed their clinical and immune traits (including innate and adaptive responses). The immune parameters were obtained by flow cytometry. Finally, we established a model that can better distinguished CHB patients who need treatment through machine learning and LASSO regression of serological and immune parameters. RESULTS Through a series of analyses, we selected four important clinical parameters (ALT, HBV DNA, the Fibroscan value, and the A/G ratio) and four immune indicators (NKbright + NKp44+, NKbright + NKG2A+, NKT+GranzymeB+, and CD3 + CD107a + ) from more than 200 variables and then successfully established a mathematical model with high sensitivity and specificity to better screen out antiviral treatment candidates from all CHB patients. CONCLUSIONS Our results developed a refined model to better screen out antiviral treatment candidates from all CHB patients by combining common clinical parameters and important immune indicators, including innate and adaptive immunity. These findings provide more information for improving treatment guidelines and have potential implications for the timing of antiviral therapy to achieve better virus control and reduce the occurrence of end-stage liver disease.
Collapse
Affiliation(s)
- Xiaoyan Li
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Yurong Gu
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Chunhong Liao
- Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Xinyi Ma
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Yanhua Bi
- Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Yifan Lian
- Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
| | - Yuehua Huang
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China; Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
| |
Collapse
|
|
5
|
Broholm M, Mathiasen AS, Apol ÁD, Weis N. The Adaptive Immune Response in Hepatitis B Virus-Associated Hepatocellular Carcinoma Is Characterized by Dysfunctional and Exhausted HBV-Specific T Cells. Viruses 2024; 16:707. [PMID: 38793588 PMCID: PMC11125979 DOI: 10.3390/v16050707] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Revised: 04/25/2024] [Accepted: 04/26/2024] [Indexed: 05/26/2024] Open
Abstract
This systematic review investigates the immunosuppressive environment in HBV-associated hepatocellular carcinoma (HCC), characterized by dysfunctional and exhausted HBV-specific T cells alongside an increased infiltration of HBV-specific CD4+ T cells, particularly regulatory T cells (Tregs). Heightened expression of checkpoint inhibitors, notably PD-1, is linked with disease progression and recurrence, indicating its potential as both a prognostic indicator and a target for immunotherapy. Nevertheless, using PD-1 inhibitors has shown limited effectiveness. In a future perspective, understanding the intricate interplay between innate and adaptive immune responses holds promise for pinpointing predictive biomarkers and crafting novel treatment approaches for HBV-associated HCC.
Collapse
Affiliation(s)
- Malene Broholm
- Department of Infectious Disease, Copenhagen University Hospital, 2650 Hvidovre, Denmark
| | - Anne-Sofie Mathiasen
- Department of Infectious Disease, Copenhagen University Hospital, 2650 Hvidovre, Denmark
| | - Ása Didriksen Apol
- Department of Infectious Disease, Copenhagen University Hospital, 2650 Hvidovre, Denmark
| | - Nina Weis
- Department of Infectious Disease, Copenhagen University Hospital, 2650 Hvidovre, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, 2300 Copenhagen, Denmark
| |
Collapse
|
|
6
|
Ajith A, Merimi M, Arki MK, Hossein-khannazer N, Najar M, Vosough M, Sokal EM, Najimi M. Immune regulation and therapeutic application of T regulatory cells in liver diseases. Front Immunol 2024; 15:1371089. [PMID: 38571964 PMCID: PMC10987744 DOI: 10.3389/fimmu.2024.1371089] [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: 01/16/2024] [Accepted: 02/28/2024] [Indexed: 04/05/2024] Open
Abstract
CD4+ CD25+ FOXP3+ T regulatory cells (Tregs) are a subset of the immunomodulatory cell population that can inhibit both innate and adaptive immunity by various regulatory mechanisms. In hepatic microenvironment, proliferation, plasticity, migration, and function of Tregs are interrelated to the remaining immune cells and their secreted cytokines and chemokines. In normal conditions, Tregs protect the liver from inflammatory and auto-immune responses, while disruption of this crosstalk between Tregs and other immune cells may result in the progression of chronic liver diseases and the development of hepatic malignancy. In this review, we analyze the deviance of this protective nature of Tregs in response to chronic inflammation and its involvement in inducing liver fibrosis, cirrhosis, and hepatocellular carcinoma. We will also provide a detailed emphasis on the relevance of Tregs as an effective immunotherapeutic option for autoimmune diseases, liver transplantation, and chronic liver diseases including liver cancer.
Collapse
Affiliation(s)
- Ananya Ajith
- Laboratory of Pediatric Hepatology and Cell Therapy, Institute of Experimental and Clinical Research (IREC), UCLouvain, Brussels, Belgium
| | - Makram Merimi
- Genetics and Immune Cell Therapy Unit, LBBES Laboratory, Faculty of Sciences, University Mohammed Premier, Oujda, Morocco
| | - Mandana Kazem Arki
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Nikoo Hossein-khannazer
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mehdi Najar
- Osteoarthritis Research Unit, Department of Medicine, University of Montreal Hospital Research Center (CRCHUM), Montreal, QC, Canada
- Faculty of Medicine, Université Libre de Bruxelles, Brussels, Belgium
| | - Massoud Vosough
- Department of Regenerative Medicine, Cell Science Research Centre, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
- Experimental Cancer Medicine, Institution for Laboratory Medicine, Karolinska Institute, Huddinge, Sweden
| | - Etienne Marc Sokal
- Laboratory of Pediatric Hepatology and Cell Therapy, Institute of Experimental and Clinical Research (IREC), UCLouvain, Brussels, Belgium
| | - Mustapha Najimi
- Laboratory of Pediatric Hepatology and Cell Therapy, Institute of Experimental and Clinical Research (IREC), UCLouvain, Brussels, Belgium
| |
Collapse
|
|
7
|
Sun L, Hui F, Tang GY, Shen HL, Cao XL, Gao JX, Li LF. Selective degradation of PL2L60 by metabolic stresses‑induced autophagy suppresses multi‑cancer growth. Oncol Rep 2024; 51:41. [PMID: 38624021 PMCID: PMC10823339 DOI: 10.3892/or.2024.8700] [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: 06/22/2023] [Accepted: 11/08/2023] [Indexed: 04/17/2024] Open
Abstract
It has been reported that PL2L60 proteins, a product of PIWIL2 gene which might be activated by an intragenic promoter, could mediate a common pathway specifically for tumorigenesis. In the present study, it was further identified by using western blot assay that the PL2L60 proteins could be degraded in cancer cells through a mechanism of selective autophagy in response to oxidative stress. The PL2L60 was downregulated in various types of cancer cells under the hypoxic condition independently of HIF‑1α, resulting in apoptosis of cancer cells. Inhibition of autophagy by small interfering RNA targeting of either Beclin‑1 (BECN1) or Atg5 resulted in restoration of PL2L60 expression in hypoxic cancer cell. The hypoxic degradation of PL2L60 was also blocked by the attenuation of the autophagosome membrane protein Atg8/microtubule‑associated protein 1 light chain 3 (LC3) or autophagy cargo protein p62 expression. Surprisingly, Immunofluorescence analysis demonstrated that LC3 could be directly bound to PL2L60 and was required for the transport of PL2L60 from the nucleus to the cytoplasm for lysosomal flux under basal or activated autophagy in cancer cells. Moreover, flow cytometric analysis displayed that knocking down of PL2L60 mRNA but not PIWIL2 mRNA effectively inhibited cancer cell proliferation and promoted apoptosis of cancer cells. The similar results were obtained from in vivo tumorigenic experiment, in which PL2L60 downregulation in necroptosis areas was confirmed by immunohistochemistry. These results suggested that various cancer could be suppressed by promoting autophagy. The present study revealed a key role of autophagic degradation of PL2L60 in hypoxia‑induced cancer cell death, which could be used as a novel therapeutic target of cancer.
Collapse
Affiliation(s)
- Lei Sun
- The State Key Laboratory of Oncogenes and Related Genes, and The Laboratory of Tumorigenesis and Immunity, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, PuDong, Shanghai 200127, P.R. China
- Department of Oncology, First Affiliated Hospital of Weifang Medical University, Weifang, Shandong 261000, P.R. China
| | - Fu Hui
- Department of Oncology, First Affiliated Hospital of Weifang Medical University, Weifang, Shandong 261000, P.R. China
| | - Gao-Yan Tang
- Department of Oncology, First Affiliated Hospital of Weifang Medical University, Weifang, Shandong 261000, P.R. China
| | - Hai-Lian Shen
- Sam and Ann Barshop Institute for Longevity of Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX 78292, USA
| | - Xue-Lei Cao
- Department of Clinical Laboratory, Qi Lu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China
| | - Jian-Xin Gao
- The State Key Laboratory of Oncogenes and Related Genes, and The Laboratory of Tumorigenesis and Immunity, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, PuDong, Shanghai 200127, P.R. China
| | - Lin-Feng Li
- The State Key Laboratory of Oncogenes and Related Genes, and The Laboratory of Tumorigenesis and Immunity, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, PuDong, Shanghai 200127, P.R. China
| |
Collapse
|
|
8
|
Yang K, Sun B, Zhang S, Pan Y, Fang J. RDW-SD is Superior to RDW-CV in Reflecting Liver Fibrosis Stage in Patients with Chronic Hepatitis B. Infect Drug Resist 2023; 16:6881-6891. [PMID: 37920477 PMCID: PMC10619233 DOI: 10.2147/idr.s427047] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Accepted: 09/18/2023] [Indexed: 11/04/2023] Open
Abstract
Purpose The clinical significance of the red blood cell distribution width (RDW)-coefficient of variation (RDW-CV) has been recognized in numerous diseases, but few studies have investigated the usefulness of RDW-standard deviation (RDW-SD). This study aimed to compare the utility of RDW-SD and RDW-CV in evaluating liver fibrosis stage in patients with chronic hepatitis B (CHB). Patients and Methods In this retrospective study, we enrolled 720 treatment-naïve CHB patients and 578 healthy controls, and evaluated their clinical parameters. In CHB patients, the associations between RDW-CV and liver fibrosis stage were analyzed as compared to RDW-SD using one-way analysis of variance (ANOVA), Spearman's rank correlation, student's t-test, binary logistic regression, and receiver operating characteristic (ROC) curve. Results RDW-SD, rather than RDW-CV was significantly elevated in CHB patients compared with healthy controls. Correlation analysis showed a stronger association between RDW-SD and liver fibrosis stage than RDW-CV in CHB patients. RDW-CV and RDW-SD are both independent predictors of significant fibrosis. For the diagnosis of significant fibrosis, the area under the receiver operating characteristic curve (AUC) for RDW-CV was 0.599, while for RDW-SD, it was 0.706. RDW-to-platelet ratio (RPR), a novel index for liver fibrosis calculated as RDW-CV/platelet, exhibited an AUC of 0.730. This AUC increased to 0.752 when RDW-CV in the RPR formula was replaced with RDW-SD. Additionally, subgroup analyses based on age, gender, and HBeAg status showed that the AUC for RDW-SD in diagnosing significant fibrosis was significantly greater than that for RDW-CV, with statistically significant differences. Conclusion RDW-SD showed superiority in reflecting liver fibrosis stage and diagnosing liver significant fibrosis than RDW-CV in treatment-naïve CHB patients.
Collapse
Affiliation(s)
- Kai Yang
- Department of Medical Technology, Anhui Medical College, Hefei, Anhui, 230601, People’s Republic of China
| | - Beibei Sun
- Department of Clinical Laboratory, the Second Hospital of Anhui Medical University, Hefei, Anhui, 230601, People’s Republic of China
| | - Shicheng Zhang
- School of Public Health and Health Management, Anhui Medical College, Hefei, Anhui, 230601, People’s Republic of China
| | - Ying Pan
- Department of Medical Technology, Anhui Medical College, Hefei, Anhui, 230601, People’s Republic of China
| | - Jun Fang
- Faculty of Pharmaceutical Science, Sojo University, Kumamoto, 860-0082, Japan
| |
Collapse
|
|
9
|
Zhao L, Li J, Mo G, Cao D, Li C, Huang G, Jiang L, Chen G, Yao H, Peng X. Recombinant protein EBI3 attenuates Clonorchis sinensis-induced liver fibrosis by inhibiting hepatic stellate cell activation in mice. Parasit Vectors 2023; 16:246. [PMID: 37480105 PMCID: PMC10360228 DOI: 10.1186/s13071-023-05863-5] [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: 03/01/2023] [Accepted: 07/03/2023] [Indexed: 07/23/2023] Open
Abstract
BACKGROUND Chronic infection with Clonorchis sinensis can cause hepatobiliary fibrosis and even lead to hepatobiliary carcinoma. Epstein-Barr virus-induced gene 3 protein (EBI3) is a subunit of interleukin 35, which can regulate inflammatory response and the occurrence of fibrotic diseases. Previous studies have reported that the expression of EBI3 in the serum of patients with liver cirrhosis is reduced. The present study aims to investigate the biological effects of EBI3 on liver fibrosis caused by C. sinensis and the underlying molecular mechanisms. METHODS We first established a mouse model of liver fibrosis induced by C. sinensis infection and then measured the serum expression of EBI3 during the inflammatory and fibrotic phase. GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway analyses were performed to investigate the potential role of EBI3 in liver fibrosis by regulating the extracellular matrix structural constituent and collagen catabolic process. Recombinant protein EBI3 (rEBI3) was added to hepatic stellate cells (HSCs) in vitro with C. sinensis antigen to explore its function. Finally, the therapeutic effect of rEBI3 was verified by intravenous injection into C. sinensis-infected mice. RESULTS The results showed that the serum expression of EBI3 increased in the inflammatory response phase but decreased in the fibrotic phase. The excretory-secretory products of C. sinensis (Cs.ESP) were able to stimulate HSC activation, while rEBI3 reduced the activation of HSCs induced by Cs.ESP. Also, the protein expression of gp130 and downstream protein expressions of JAK1, p-JAK1, STAT3 and p-STAT3 in HSCs were increased after rEBI3 incubation. Finally, intravenously injected rEBI3 inhibited hepatic epithelial-mesenchymal transition in C. sinensis-infected mice by inhibiting HSC activation and reducing liver injury. CONCLUSION This study confirms that rEBI3 can attenuate C. sinensis-induced liver fibrosis by inhibiting HSC activation and may be one of the potential treatments for liver fibrosis.
Collapse
Affiliation(s)
- Lei Zhao
- Guangxi University Key Laboratory of Pathogenic Biology, Guilin Medical University, Guilin, Guangxi, People's Republic of China
| | - Jia Li
- Guangxi University Key Laboratory of Pathogenic Biology, Guilin Medical University, Guilin, Guangxi, People's Republic of China
| | - Gang Mo
- Guangxi University Key Laboratory of Pathogenic Biology, Guilin Medical University, Guilin, Guangxi, People's Republic of China
| | - Deping Cao
- Guangxi University Key Laboratory of Pathogenic Biology, Guilin Medical University, Guilin, Guangxi, People's Republic of China
| | - Chun Li
- Guangxi University Key Laboratory of Pathogenic Biology, Guilin Medical University, Guilin, Guangxi, People's Republic of China
| | - Guoyang Huang
- Guangxi University Key Laboratory of Pathogenic Biology, Guilin Medical University, Guilin, Guangxi, People's Republic of China
| | - Liping Jiang
- Guangxi University Key Laboratory of Pathogenic Biology, Guilin Medical University, Guilin, Guangxi, People's Republic of China
| | - Gen Chen
- Guangxi University Key Laboratory of Pathogenic Biology, Guilin Medical University, Guilin, Guangxi, People's Republic of China
| | - Hongbing Yao
- Second Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, People's Republic of China
| | - Xiaohong Peng
- Guangxi University Key Laboratory of Pathogenic Biology, Guilin Medical University, Guilin, Guangxi, People's Republic of China.
- Guangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, The Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, People's Republic of China.
| |
Collapse
|
|
10
|
Wu LL, Li XY, Deng K, Lin BL, Deng H, Xie DY, Zhang GL, Zhao QY, Mo ZS, Huang YH, Gao ZL. Predictive value of Th17 and Treg cells at baseline for HBsAg loss in chronic hepatitis B patients with low HBsAg quantification treated with pegylated interferon and nucleos(t)ide analogue. LIVER RESEARCH 2023; 7:136-144. [PMID: 39958952 PMCID: PMC11791923 DOI: 10.1016/j.livres.2023.04.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Revised: 12/23/2022] [Accepted: 04/25/2023] [Indexed: 01/02/2025]
Abstract
Background and aims The primary goal of chronic hepatitis B (CHB) treatment is to reduce hepatitis B surface antigen (HBsAg). T helper 17 (Th17) and regulatory T (Treg) cells are essential for the development of CHB. However, how Th17 and Treg cells contribute to HBsAg loss is still unknown. Therefore, this study aimed to search for the predictive value of Th17 and Treg cells for HBsAg loss in CHB patients with low HBsAg quantification. Methods The study included 99 hepatitis B e antigen (HBeAg)-negative CHB patients who had completed a year of nucleos(t)ide analogue (NA) monotherapy and had received both NA and pegylated interferon (PEG-IFN) treatment for less than 96 weeks (96 wk). In the cured group, 48 patients lost HBsAg within 48 wk, while 51 patients did not (uncured group). Blood samples and clinical data were collected for research. Results During PEG-IFN and NA combination therapy, the proportion of Th17 cells in the cured group increased significantly, while the proportion of Treg cells in the uncured group increased. From 0 to 24 wk, the proportion of Th17 cells in the cured group was significantly higher than in the uncured group, while the opposite was true for Treg cells. Patients with alanine aminotransferase (ALT) ≥ 2.5 upper limit of normal (ULN) at 12 wk had a higher proportion of Th17 cells and a lower proportion of Treg cells than those with ALT <2.5 ULN at 12 wk. Additionally, the proportion of Th17 cells is inversely associated with the level of HBsAg, whereas the level of Treg cells is positively related to HBsAg quantification. The clinical cure index, including age, HBsAg quantification, and the proportions of Th17 and Treg cells, had a higher area under the curve (0.957) for predicting HBsAg loss when compared to the proportions of Th17 and Treg cells and HBsAg quantification alone. Conclusions Combined with quantification of HBsAg, the proportions of Th17 cells and Treg cells at baseline can be used as good predictors of HBsAg loss in patients with low HBsAg quantification treated with NA and PEG-IFN.
Collapse
Affiliation(s)
- Li-Li Wu
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Xiao-Yan Li
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Kai Deng
- Institute of Human Virology, Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Bing-Liang Lin
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Hong Deng
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Dong-Ying Xie
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Geng-Lin Zhang
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Qi-Yi Zhao
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Zhi-Shuo Mo
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Yue-Hua Huang
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Zhi-Liang Gao
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
- Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou, Guangdong, China
| |
Collapse
|
|
11
|
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.
Collapse
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
| |
Collapse
|
|
12
|
Han HT, Jin WL, Li X. Mesenchymal stem cells-based therapy in liver diseases. MOLECULAR BIOMEDICINE 2022; 3:23. [PMID: 35895169 PMCID: PMC9326420 DOI: 10.1186/s43556-022-00088-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Accepted: 06/20/2022] [Indexed: 12/24/2022] Open
Abstract
Multiple immune cells and their products in the liver together form a complex and unique immune microenvironment, and preclinical models have demonstrated the importance of imbalances in the hepatic immune microenvironment in liver inflammatory diseases and immunocompromised liver diseases. Various immunotherapies have been attempted to modulate the hepatic immune microenvironment for the purpose of treating liver diseases. Mesenchymal stem cells (MSCs) have a comprehensive and plastic immunomodulatory capacity. On the one hand, they have been tried for the treatment of inflammatory liver diseases because of their excellent immunosuppressive capacity; On the other hand, MSCs have immune-enhancing properties in immunocompromised settings and can be modified into cellular carriers for targeted transport of immune enhancers by genetic modification, physical and chemical loading, and thus they are also used in the treatment of immunocompromised liver diseases such as chronic viral infections and hepatocellular carcinoma. In this review, we discuss the immunological basis and recent strategies of MSCs for the treatment of the aforementioned liver diseases. Specifically, we update the immune microenvironment of the liver and summarize the distinct mechanisms of immune microenvironment imbalance in inflammatory diseases and immunocompromised liver diseases, and how MSCs can fully exploit their immunotherapeutic role in liver diseases with both immune imbalance patterns.
Collapse
Affiliation(s)
- Heng-Tong Han
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, 730000, P. R, China
| | - Wei-Lin Jin
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, 730000, P. R, China
- Medical Frontier Innovation Research Center, The First Hospital of Lanzhou University, No. 1 West Donggang Road, Lanzhou, 730000, People's Republic of China
| | - Xun Li
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, 730000, P. R, China.
- Medical Frontier Innovation Research Center, The First Hospital of Lanzhou University, No. 1 West Donggang Road, Lanzhou, 730000, People's Republic of China.
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, 730000, People's Republic of China.
- Key Laboratory Biotherapy and Regenerative Medicine of Gansu Province, Lanzhou, 730000, People's Republic of China.
| |
Collapse
|
|
13
|
Stella L, Santopaolo F, Gasbarrini A, Pompili M, Ponziani FR. Viral hepatitis and hepatocellular carcinoma: From molecular pathways to the role of clinical surveillance and antiviral treatment. World J Gastroenterol 2022; 28:2251-2281. [PMID: 35800182 PMCID: PMC9185215 DOI: 10.3748/wjg.v28.i21.2251] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 12/08/2021] [Accepted: 04/26/2022] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a global health challenge. Due to the high prevalence in low-income countries, hepatitis B virus (HBV) and hepatitis C virus infections remain the main risk factors for HCC occurrence, despite the increasing frequencies of non-viral etiologies. In addition, hepatitis D virus coinfection increases the oncogenic risk in patients with HBV infection. The molecular processes underlying HCC development are complex and various, either independent from liver disease etiology or etiology-related. The reciprocal interlinkage among non-viral and viral risk factors, the damaged cellular microenvironment, the dysregulation of the immune system and the alteration of gut-liver-axis are known to participate in liver cancer induction and progression. Oncogenic mechanisms and pathways change throughout the natural history of viral hepatitis with the worsening of liver fibrosis. The high risk of cancer incidence in chronic viral hepatitis infected patients compared to other liver disease etiologies makes it necessary to implement a proper surveillance, both through clinical-biochemical scores and periodic ultrasound assessment. This review aims to outline viral and microenvironmental factors contributing to HCC occurrence in patients with chronic viral hepatitis and to point out the importance of surveillance programs recommended by international guidelines to promote early diagnosis of HCC.
Collapse
Affiliation(s)
- Leonardo Stella
- Internal Medicine and Gastroenterology, Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome 00168, Italy
| | - Francesco Santopaolo
- Internal Medicine and Gastroenterology, Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome 00168, Italy
| | - Antonio Gasbarrini
- Internal Medicine and Gastroenterology, Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome 00168, Italy
| | - Maurizio Pompili
- Internal Medicine and Gastroenterology, Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome 00168, Italy
| | - Francesca Romana Ponziani
- Internal Medicine and Gastroenterology, Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome 00168, Italy
| |
Collapse
|
|
14
|
高 鹏, 雒 艳, 李 俊, 陈 琳, 毛 小. [Effects of hepatitis B virus on Th17, Treg and Th17/Treg ratio in different alanine aminetransferase stages]. BEIJING DA XUE XUE BAO. YI XUE BAN = JOURNAL OF PEKING UNIVERSITY. HEALTH SCIENCES 2022; 54:272-277. [PMID: 35435191 PMCID: PMC9069043 DOI: 10.19723/j.issn.1671-167x.2022.02.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 01/06/2020] [Indexed: 06/14/2023]
Abstract
OBJECTIVE To evaluate the effects of hepatitis B virus (HBV) on helper T lymphocytes 17 (Th17), regulatory T lymphocyte (Treg) and Th17/Treg ratio in chronic hepatitis B patients in different alanine aminetransferase (ALT) stages. METHODS In the study, 336 chronic hepatitis B patients in the first hospital of Lanzhou University were analyzed. The hepatitis B antigen antibody parameters were measured by chemiluminescence immunoassay analyzer, the liver function parameters were measured by automatic biochemical analyzer, the HBV loads were measured by quantitative PCR, Th17, Treg and Th17/Treg ratios were detected by flow cytometry. Among them, 111 cases (ALT < 40 U/L) of ALT were normal hepatitis B, 108 cases of chronic hepatitis B with ALT above normal upper limit and < 2 times higher (40 U/L≤ALT < 80 U/L), and 117 cases of chronic hepatitis B with ALT above 2 times normal upper limit (80 U/L≤ALT). According to the viral load, they were divided into low replication group with HBV DNA < 4.0 lg copies/mL, medium replication group with 4.0 lg copies/mL≤HBV DNA < 6.0 lg copies/mL and high replication group with HBV DNA ≥ 6.0 lg copies / mL. Dunnett T3 variance analysis were used to analyze the effects of HBV on Th17, Treg and Th17/Treg ratio in the chronic hepatitis B patients in different ALT stages. The changes of virological and immunological indexes before and after treatment were observed for 24 weeks of antiviral therapy in the hepatitis B patients with ALT≥double upper limit of normal group. RESULTS In the ALT normal group, different virus load HBV had minor effects on Th17, Treg and Th17/Treg ratio. In the ALT≥2 times upper limit of normal group, with the virus load increased, Th17 (3.18%±0.79% in low replication group, 3.78%±0.92% in medium replication group and 4.57%±1.15% in high replication group), Treg cells (5.52%±1.58% in low replication group, 5.89%±1.84% in medium replication group and 6.37%±2.35% in high replication group) and their ratio Th17/Treg (0.57±0.25 in low replication group, 0.65±0.29 in medium replication group and 0.73±0.36 in high replication group) were significantly increased (P < 0.05). After entecavir treatment 24 weeks, the patient' s HBV-DNA decreased significantly, Th17 (3.89%±1.02% vs. 2.06%±0.46%), Treg (6.02%±2.03% vs. 5.06%±1.25%), Th17/Treg ratio (0.65±0.28 vs. 0.41±0.14) decreased significantly (P < 0.05). CONCLUSION Investigation on the effects of HBV on Th17 and Treg cells and their ratios in different ALT states can clarify the effects of HBV on the body from the immunological perspective and can further understand the ALT grouping for antiviral treatment theoretical significance, which is helpful for clinical treatment.
Collapse
Affiliation(s)
- 鹏 高
- 兰州大学第一医院传染病研究室，兰州 730000Infectious Disease Research Institute, First Hospital of Lanzhou University, Lanzhou 730000, China
| | - 艳萍 雒
- 兰州大学基础医学院免疫教研室，兰州 730000Department of Immunology, Medicine College of Lanzhou University, Lanzhou 730000, China
| | - 俊峰 李
- 兰州大学第一医院传染病研究室，兰州 730000Infectious Disease Research Institute, First Hospital of Lanzhou University, Lanzhou 730000, China
| | - 琳 陈
- 兰州大学第一医院传染科，兰州 730000Department of Infection, First Hospital of Lanzhou University, Lanzhou 730000, China
| | - 小荣 毛
- 兰州大学第一医院传染科，兰州 730000Department of Infection, First Hospital of Lanzhou University, Lanzhou 730000, China
| |
Collapse
|
|
15
|
Chen C, Guan J, Gu X, Chu Q, Zhu H. Prostaglandin E2 and Receptors: Insight Into Tumorigenesis, Tumor Progression, and Treatment of Hepatocellular Carcinoma. Front Cell Dev Biol 2022; 10:834859. [PMID: 35356289 PMCID: PMC8959932 DOI: 10.3389/fcell.2022.834859] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Accepted: 02/07/2022] [Indexed: 12/11/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a common primary liver cancer with ∼750,000 annual incidence rates globally. PGE2, usually known as a pro-inflammatory cytokine, is over-expressed in various human malignancies including HCC. PGE2 binds to EP receptors in HCC cells to influence tumorigenesis or enhance tumor progression through multiple pathways such as EP1-PKC-MAPK, EP2-PKA-GSK3β, and EP4-PKA-CREB. In the progression of hepatocellular carcinoma, PGE2 can promote the proliferation and migration of liver cancer cells by affecting hepatocytes directly and the tumor microenvironment (TME) through ERK/COX-2/PGE2 signal pathway in hepatic stellate cells (HSC). For the treatment of hepatocellular carcinoma, there are drugs such as T7 peptide and EP1 antagonist ONO-8711 targeting Cox-2/PGE2 axis to inhibit tumor progression. In conclusion, PGE2 has been shown to be a traditional target with pleiotropic effects in tumorigenesis and progression of HCC that could be used to develop a new potential clinical impact. For the treatment study focusing on the COX-PGE2 axis, the exclusive usage of non-steroidal anti-inflammatory agents (NSAIDs) or COX-2-inhibitors may be replaced by a combination of selective EP antagonists and traditional anti-tumoral drugs to alleviate severe side effects and achieve better outcomes.
Collapse
|
|
16
|
Zhang M, Zhao H, Gao H. Interleukin-24 Limits Tumor-Infiltrating T Helper 17 Cell Response in Patients with Hepatitis B Virus-Related Hepatocellular Carcinoma. Viral Immunol 2022; 35:212-222. [PMID: 35099297 DOI: 10.1089/vim.2021.0174] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Affiliation(s)
- Minqi Zhang
- Department of General Surgery, Daqing People's Hospital, Daqing, People's Republic of China
| | - Haifeng Zhao
- Department of General Surgery, Daqing People's Hospital, Daqing, People's Republic of China
| | - Honglei Gao
- Department of General Surgery, Daqing People's Hospital, Daqing, People's Republic of China
| |
Collapse
|
|
17
|
Yang F, Li H, Li Y, Hao Y, Wang C, Jia P, Chen X, Ma S, Xiao Z. Crosstalk between hepatic stellate cells and surrounding cells in hepatic fibrosis. Int Immunopharmacol 2021; 99:108051. [PMID: 34426110 DOI: 10.1016/j.intimp.2021.108051] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 07/28/2021] [Accepted: 08/04/2021] [Indexed: 02/08/2023]
Abstract
Hepatic fibrosis represents as a dynamic pathological process characterized by the net accumulation of extracellular matrix in the progression of various chronic liver diseases, including viral hepatitis, alcoholic liver disease, and metabolic associated fatty liver disease (MAFLD). Activation of hepatic stellate cells (HSCs) is well-defined to play a central role in the initiation and progression of hepatic fibrosis. However, the activation of HSCs is affected by the complicated microenvironments in liver, which largely attributes to the communication between hepatocytes and multiple tissue-resident cells, including sinusoidal endothelial cells, bile duct epithelial cells, platelets, T cells, B cells, macrophages, natural killer cells, neutrophils, dendritic cells, in the direct or indirect mechanisms. Cellular crosstalk between HSCs and surrounding cells contributes to the activation of HSCs and the progression of hepatic fibrosis. Currently, accumulating evidence have proven the complexity and plasticity of HSCs activation, and further clarification of cellular communication between HSCs and surrounding cells will provide sufficient clue to the development of novel diagnostic methods and therapeutic strategies for hepatic fibrosis.
Collapse
Affiliation(s)
- Fangming Yang
- Department of Digestive Diseases, The First Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou, China
| | - Heng Li
- Laboratory of Anti-inflammation and Immunopharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Yanmin Li
- Department of Digestive Diseases, The First Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou, China
| | - Yaokun Hao
- Department of Digestive Diseases, The First Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou, China
| | - Chenxiao Wang
- Department of Digestive Diseases, The First Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou, China
| | - Pan Jia
- Department of Digestive Diseases, The First Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou, China
| | - Xinju Chen
- Department of Digestive Diseases, The First Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou, China.
| | - Suping Ma
- Department of Digestive Diseases, The First Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou, China.
| | - Zhun Xiao
- Department of Digestive Diseases, The First Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou, China.
| |
Collapse
|
|
18
|
Rosenthal SB, Liu X, Ganguly S, Dhar D, Pasillas MP, Ricciardelli E, Li RZ, Troutman TD, Kisseleva T, Glass CK, Brenner DA. Heterogeneity of HSCs in a Mouse Model of NASH. Hepatology 2021; 74:667-685. [PMID: 33550587 PMCID: PMC8346581 DOI: 10.1002/hep.31743] [Citation(s) in RCA: 90] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Revised: 11/24/2020] [Accepted: 12/23/2020] [Indexed: 12/29/2022]
Abstract
BACKGROUND AND AIMS In clinical and experimental NASH, the origin of the scar-forming myofibroblast is the HSC. We used foz/foz mice on a Western diet to characterize in detail the phenotypic changes of HSCs in a NASH model. APPROACH AND RESULTS We examined the single-cell expression profiles (scRNA sequencing) of HSCs purified from the normal livers of foz/foz mice on a chow diet, in NASH with fibrosis of foz/foz mice on a Western diet, and in livers during regression of NASH after switching back to a chow diet. Selected genes were analyzed using immunohistochemistry, quantitative real-time PCR, and short hairpin RNA knockdown in primary mouse HSCs. Our analysis of the normal liver identified two distinct clusters of quiescent HSCs that correspond to their acinar position of either pericentral vein or periportal vein. The NASH livers had four distinct HSC clusters, including one representing the classic fibrogenic myofibroblast. The three other HSC clusters consisted of a proliferating cluster, an intermediate activated cluster, and an immune and inflammatory cluster. The livers with NASH regression had one cluster of inactivated HSCs, which was similar to, but distinct from, the quiescent HSCs. CONCLUSIONS Analysis of single-cell RNA sequencing in combination with an interrogation of previous studies revealed an unanticipated heterogeneity of HSC phenotypes under normal and injured states.
Collapse
Affiliation(s)
- Sara Brin Rosenthal
- Center for Computational Biology and BioinformaticsUniversity of California, San DiegoLa JollaCA.,Department of MedicineUniversity of California, San DiegoLa JollaCA
| | - Xiao Liu
- Department of MedicineUniversity of California, San DiegoLa JollaCA.,Department of SurgeryUniversity of California, San DiegoLa JollaCA
| | | | - Debanjan Dhar
- Department of MedicineUniversity of California, San DiegoLa JollaCA
| | - Martina P Pasillas
- Department of Cellular and Molecular MedicineUniversity of California, San DiegoLa JollaCA
| | | | - Rick Z Li
- Department of Cellular and Molecular MedicineUniversity of California, San DiegoLa JollaCA
| | - Ty D Troutman
- Department of MedicineUniversity of California, San DiegoLa JollaCA
| | | | - Christopher K Glass
- Department of MedicineUniversity of California, San DiegoLa JollaCA.,Department of Cellular and Molecular MedicineUniversity of California, San DiegoLa JollaCA
| | - David A Brenner
- Department of MedicineUniversity of California, San DiegoLa JollaCA
| |
Collapse
|
|
19
|
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.
Collapse
Affiliation(s)
| | - Jae-Youn Cheong
- Correspondence: ; Tel.: +82-31-219-6939; Fax: +82-31-219-5999
| |
Collapse
|
|
20
|
Wegrzyniak O, Rosestedt M, Eriksson O. Recent Progress in the Molecular Imaging of Nonalcoholic Fatty Liver Disease. Int J Mol Sci 2021; 22:7348. [PMID: 34298967 PMCID: PMC8306605 DOI: 10.3390/ijms22147348] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Revised: 06/30/2021] [Accepted: 07/06/2021] [Indexed: 12/12/2022] Open
Abstract
Pathological fibrosis of the liver is a landmark feature in chronic liver diseases, including nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). Diagnosis and assessment of progress or treatment efficacy today requires biopsy of the liver, which is a challenge in, e.g., longitudinal interventional studies. Molecular imaging techniques such as positron emission tomography (PET) have the potential to enable minimally invasive assessment of liver fibrosis. This review will summarize and discuss the current status of the development of innovative imaging markers for processes relevant for fibrogenesis in liver, e.g., certain immune cells, activated fibroblasts, and collagen depositions.
Collapse
Affiliation(s)
- Olivia Wegrzyniak
- Science for Life Laboratory, Department of Medicinal Chemistry, Uppsala University, SE-751 83 Uppsala, Sweden; (O.W.); (M.R.)
| | - Maria Rosestedt
- Science for Life Laboratory, Department of Medicinal Chemistry, Uppsala University, SE-751 83 Uppsala, Sweden; (O.W.); (M.R.)
| | - Olof Eriksson
- Science for Life Laboratory, Department of Medicinal Chemistry, Uppsala University, SE-751 83 Uppsala, Sweden; (O.W.); (M.R.)
- Antaros Medical AB, SE-431 83 Mölndal, Sweden
| |
Collapse
|
|
21
|
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.
Collapse
|
|
22
|
Liu S, Liu Z, Shan Z, Liu Y, Chen T, Fang L, Quan H. Skewed Th17/Treg balance during progression and malignant transformation of oral submucous fibrosis. Oral Dis 2021; 28:2119-2130. [PMID: 33749974 DOI: 10.1111/odi.13853] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Revised: 03/01/2021] [Accepted: 03/16/2021] [Indexed: 11/28/2022]
Abstract
OBJECTIVES The aim of our study was to determine the impact of Th17/Treg imbalance on the progression and malignant transformation of oral submucosal fibrosis (OSF). MATERIALS AND METHODS To assess Th17 and Treg expression, overall 52 peripheral blood samples from OSF, oral squamous cell carcinoma (OSCC) patients, and healthy donors were analyzed by flow cytometry. Thirty normal oral mucosa, 72 OSF, and 90 OSCC samples were analyzed by immunohistochemistry. RESULTS In peripheral blood samples, in OSCC with OSF, Th17 and Treg expression were significantly higher than those in OSF and OSCC without OSF as confirmed by immunohistochemistry. During OSF progression, Th17 and Th17/Treg ratio showed an increasing trend, while Treg expression showed a decreasing trend. Treg expression was significantly higher in OSCC with OSF than in OSF and OSCC without OSF, whereas the Th17/Treg ratio was significantly lower in OSCC with OSF. Treg expression was significantly correlated with smoking and clinical stage. Th17/Treg ratio was significantly associated with tumor size, lymph node metastasis, and clinical stage. A low Th17/Treg ratio was significantly associated with poor prognosis. CONCLUSIONS Th17/Treg ratio is a potential diagnostic indicator for OSF occurrence and malignant transformation and was an independent prognostic factor for OSCC.
Collapse
Affiliation(s)
- Sixuan Liu
- Hunan Key Laboratory of Oral Health Research & Hunan 3D Printing Engineering Research Center of Oral Care & Hunan Clinical Research Center of Oral Major Diseases and Oral Health Xiangya Stomatological Hospital & Xiangya School of Stomatology, Central South University, Changsha, China.,Department of Oral Maxillofacial Surgery, Xiangya Stomatological Hospital & School of Stomatology, Central South University, Changsha, China
| | - Ziyi Liu
- Hunan Key Laboratory of Oral Health Research & Hunan 3D Printing Engineering Research Center of Oral Care & Hunan Clinical Research Center of Oral Major Diseases and Oral Health Xiangya Stomatological Hospital & Xiangya School of Stomatology, Central South University, Changsha, China.,Department of Oral Maxillofacial Surgery, Xiangya Stomatological Hospital & School of Stomatology, Central South University, Changsha, China
| | - Zhongyan Shan
- Hunan Key Laboratory of Oral Health Research & Hunan 3D Printing Engineering Research Center of Oral Care & Hunan Clinical Research Center of Oral Major Diseases and Oral Health Xiangya Stomatological Hospital & Xiangya School of Stomatology, Central South University, Changsha, China.,Department of Oral Maxillofacial Surgery, Xiangya Stomatological Hospital & School of Stomatology, Central South University, Changsha, China
| | - Yuxin Liu
- Hunan Key Laboratory of Oral Health Research & Hunan 3D Printing Engineering Research Center of Oral Care & Hunan Clinical Research Center of Oral Major Diseases and Oral Health Xiangya Stomatological Hospital & Xiangya School of Stomatology, Central South University, Changsha, China.,Department of Oral Maxillofacial Surgery, Xiangya Stomatological Hospital & School of Stomatology, Central South University, Changsha, China
| | - Tianjun Chen
- Hunan Key Laboratory of Oral Health Research & Hunan 3D Printing Engineering Research Center of Oral Care & Hunan Clinical Research Center of Oral Major Diseases and Oral Health Xiangya Stomatological Hospital & Xiangya School of Stomatology, Central South University, Changsha, China.,Department of Oral Maxillofacial Surgery, Xiangya Stomatological Hospital & School of Stomatology, Central South University, Changsha, China
| | - Liangjuan Fang
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, China.,Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, China
| | - Hongzhi Quan
- Hunan Key Laboratory of Oral Health Research & Hunan 3D Printing Engineering Research Center of Oral Care & Hunan Clinical Research Center of Oral Major Diseases and Oral Health Xiangya Stomatological Hospital & Xiangya School of Stomatology, Central South University, Changsha, China.,Department of Oral Maxillofacial Surgery, Xiangya Stomatological Hospital & School of Stomatology, Central South University, Changsha, China
| |
Collapse
|
|
23
|
Xi S, Zheng X, Li X, Jiang Y, Wu Y, Gong J, Jie Y, Li Z, Cao J, Sha L, Zhang M, Chong Y. Activated Hepatic Stellate Cells Induce Infiltration and Formation of CD163 + Macrophages via CCL2/CCR2 Pathway. Front Med (Lausanne) 2021; 8:627927. [PMID: 33614685 PMCID: PMC7893116 DOI: 10.3389/fmed.2021.627927] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Accepted: 01/14/2021] [Indexed: 12/19/2022] Open
Abstract
Background: Activated hepatic stellate cells (aHSCs) regulate the function of immune cells during liver fibrosis. As major innate cells in the liver, macrophages have inducible plasticity. Nevertheless, the mechanisms through which aHSCs regulate macrophages' phenotype and function during liver fibrosis and cirrhosis remain unclear. In this study, we examined the immunoregulatory function of aHSCs during liver fibrosis and explored their role in regulating macrophage phenotype and function. Methods: A total of 96 patients with different stages of chronic hepatitis B-related liver fibrosis were recruited in the study. Metavir score system was used to evaluate the degree of fibrosis. The expression of hepatic CCL2 and M2 phenotype macrophage marker CD163 were detected by immunohistochemistry, and the relationship among hepatic CD163, CCL2, and fibrosis scores were also explored. In the in vitro model, the aHSCs isolated from human liver tissues and THP-1-derived M0-type macrophages (M0MΦ) were co-cultured to observe whether and how aHSCs regulate the phenotype and function of macrophages. To explore whether CCL2/CCR2 axis has a crucial role in macrophage phenotypic changes during liver fibrosis, we treated the M0MΦ with recombinant human CCL2 or its specific receptor antagonist INCB-3284. Furthermore, we used LX2 and TGF-β-activated LX2 to mimic the different activation statuses of aHSCs to further confirm our results. Results: In patients, the infiltration of M2 macrophages increased during the progression of liver fibrosis. Intriguingly, as a key molecule for aHSC chemotactic macrophage aggregation, CCL2 markedly up-regulated the expression of CD163 and CD206 on the macrophages, which was further confirmed by adding the CCR2 antagonist (INCB 3284) into the cell culture system. In addition, the TGF-β stimulated LX2 further confirmed that aHSCs up-regulate the expression of CD163 and CD206 on macrophages. LX2 stimulated with TGF-β could produce more CCL2 and up-regulate other M2 phenotype macrophage-specific markers, including IL-10, ARG-1, and CCR2 besides CD163 and CD206 at the gene level, indicating that the different activation status of aHSCs might affect the final phenotype and function of macrophages. Conclusions: The expression of the M2 macrophage marker increases during liver fibrosis progression and is associated with fibrosis severity. AHSCs can recruit macrophages through the CCL2/CCR2 pathway and induce M2 phenotypic transformation.
Collapse
Affiliation(s)
- Sujuan Xi
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,Key Laboratory of Tropical Disease Control, Ministry of Education, Sun Yat-sen University, Guangzhou, China.,The Reproductive Medical Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Xiaoyan Zheng
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Xiangyong Li
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yuming Jiang
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yuankai Wu
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Jiao Gong
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,Key Laboratory of Tropical Disease Control, Ministry of Education, Sun Yat-sen University, Guangzhou, China
| | - Yusheng Jie
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,Key Laboratory of Tropical Disease Control, Ministry of Education, Sun Yat-sen University, Guangzhou, China
| | - Zhanyi Li
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,Key Laboratory of Tropical Disease Control, Ministry of Education, Sun Yat-sen University, Guangzhou, China
| | - Jing Cao
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,Key Laboratory of Tropical Disease Control, Ministry of Education, Sun Yat-sen University, Guangzhou, China
| | - Liuping Sha
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Min Zhang
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,Key Laboratory of Tropical Disease Control, Ministry of Education, Sun Yat-sen University, Guangzhou, China
| | - Yutian Chong
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,Key Laboratory of Tropical Disease Control, Ministry of Education, Sun Yat-sen University, Guangzhou, China
| |
Collapse
|
|
24
|
Ouaguia L, Dufeu-Duchesne T, Leroy V, Decaens T, Reiser JB, Sosa Cuevas E, Durantel D, Valladeau-Guilemond J, Bendriss-Vermare N, Chaperot L, Aspord C. Hepatitis B virus exploits C-type lectin receptors to hijack cDC1s, cDC2s and pDCs. Clin Transl Immunology 2020; 9:e1208. [PMID: 33312564 PMCID: PMC7723857 DOI: 10.1002/cti2.1208] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2020] [Revised: 10/18/2020] [Accepted: 10/19/2020] [Indexed: 01/07/2023] Open
Abstract
Objectives C‐type lectin receptors (CLRs) are key receptors used by DCs to orchestrate responses to pathogens. During infections, the glycan–lectin interactions shape the virus–host interplay and viruses can subvert the function of CLRs to escape antiviral immunity. Recognition of virus/viral components and uptake by CLRs together with subsequent signalling cascades are crucial in initiating and shaping antiviral immunity, and decisive in the outcome of infection. Yet, the interaction of hepatitis B virus (HBV) with CLRs remains largely unknown. As HBV hijacks DC subsets and viral antigens harbour glycan motifs, we hypothesised that HBV may subvert DCs through CLR binding. Methods We investigated here the pattern of CLR expression on BDCA1+ cDC2s, BDCA2+ pDCs and BDCA3+ cDC1s from both blood and liver of HBV‐infected patients and explored the ability of HBsAg to bind DC subsets through specific CLRs. Results We highlighted for the first time that the CLR repertoire of circulating and intrahepatic cDC2s, cDC1s and pDCs was perturbed in patients with chronic HBV infection and that some CLR expression levels correlated with plasma HBsAg and HBV DNA levels. We also identified candidate CLR responsible for HBsAg binding to cDCs (CD367/DCIR/CLEC4A, CD32/FcɣRIIA) and pDCs (CD369/DECTIN1/CLEC7A, CD336/NKp44) and demonstrated that HBsAg inhibited DC functions in a CLR‐ and glycosylation‐dependent manner. Conclusion HBV may exploit CLR pathways to hijack DC subsets and escape from immune control. Such advances bring insights into the mechanisms by which HBV subverts immunity and pave the way for developing innovative therapeutic strategies to restore an efficient immune control of the infection by manipulating the viral glycan–lectin axis.
Collapse
Affiliation(s)
- Laurissa Ouaguia
- Institute for Advanced Biosciences, Immunobiology and Immunotherapy in Chronic Diseases Inserm U 1209 CNRS UMR 5309 Université Grenoble Alpes Grenoble France.,R&D Laboratory Etablissement Français du Sang Auvergne-Rhône-Alpes Grenoble France
| | - Tania Dufeu-Duchesne
- Hepato-Gastroenterology Unit CHU Grenoble Alpes Grenoble France.,Institute for Advanced Biosciences Research Center Inserm U1209/CNRS 5309/UGA Analytic Immunology of Chronic Pathologies La Tronche France
| | - Vincent Leroy
- Hepato-Gastroenterology Unit CHU Grenoble Alpes Grenoble France.,Institute for Advanced Biosciences Research Center Inserm U1209/CNRS 5309/UGA Analytic Immunology of Chronic Pathologies La Tronche France.,Université Grenoble Alpes Grenoble France
| | - Thomas Decaens
- Hepato-Gastroenterology Unit CHU Grenoble Alpes Grenoble France.,Institute for Advanced Biosciences Research Center Inserm U1209/CNRS 5309/UGA Analytic Immunology of Chronic Pathologies La Tronche France.,Université Grenoble Alpes Grenoble France
| | - Jean-Baptiste Reiser
- Institut de Biologie Structurale CNRS CEA Université Grenoble Alpes Grenoble France
| | - Eleonora Sosa Cuevas
- Institute for Advanced Biosciences, Immunobiology and Immunotherapy in Chronic Diseases Inserm U 1209 CNRS UMR 5309 Université Grenoble Alpes Grenoble France.,R&D Laboratory Etablissement Français du Sang Auvergne-Rhône-Alpes Grenoble France
| | - David Durantel
- INSERM 1052 CNRS 5286 Centre Léon Bérard Centre de Recherche en Cancérologie de Lyon Université Lyon Université Claude Bernard Lyon 1 Lyon France
| | - Jenny Valladeau-Guilemond
- INSERM 1052 CNRS 5286 Centre Léon Bérard Centre de Recherche en Cancérologie de Lyon Université Lyon Université Claude Bernard Lyon 1 Lyon France
| | - Nathalie Bendriss-Vermare
- INSERM 1052 CNRS 5286 Centre Léon Bérard Centre de Recherche en Cancérologie de Lyon Université Lyon Université Claude Bernard Lyon 1 Lyon France
| | - Laurence Chaperot
- Institute for Advanced Biosciences, Immunobiology and Immunotherapy in Chronic Diseases Inserm U 1209 CNRS UMR 5309 Université Grenoble Alpes Grenoble France.,R&D Laboratory Etablissement Français du Sang Auvergne-Rhône-Alpes Grenoble France
| | - Caroline Aspord
- Institute for Advanced Biosciences, Immunobiology and Immunotherapy in Chronic Diseases Inserm U 1209 CNRS UMR 5309 Université Grenoble Alpes Grenoble France.,R&D Laboratory Etablissement Français du Sang Auvergne-Rhône-Alpes Grenoble France
| |
Collapse
|
|
25
|
The role of intestinal microbiota, bile acids, and Th17/IL17 axis in hepatitis B virus-related liver fibrosis. Chin Med J (Engl) 2020; 133:2902-2904. [PMID: 33186134 PMCID: PMC7752688 DOI: 10.1097/cm9.0000000000001199] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
|
|
26
|
Wang W, Huang X, Fan X, Yan J, Luan J. Progress in evaluating the status of hepatitis C infection based on the functional changes of hepatic stellate cells (Review). Mol Med Rep 2020; 22:4116-4124. [PMID: 33000255 DOI: 10.3892/mmr.2020.11516] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Accepted: 08/18/2020] [Indexed: 11/06/2022] Open
Abstract
Hepatitis C virus (HCV) infection is a global public health problem. Cirrhosis and hepatocellular carcinoma are the main causes of death in patients with chronic hepatitis C (CHC) infection. Liver fibrosis is an important cause of cirrhosis and end‑stage liver disease after CHC infection. Along with the course of infection, liver fibrosis exhibits a progressive exacerbation. Hepatic stellate cells (HSCs) are involved in both physiological and pathological processes of the liver. During the chronic liver injury process, the activated HSCs transform into myofibroblasts, which are important cells in the development of liver fibrosis. At present, HCV infection still lacks specific markers for the accurate detection of the disease condition and progression. Therefore, the present review focused on HSCs, which are closely related to HCV‑infected liver fibrosis, and analyzed the changes in the HSCs, including their surface‑specific markers, cytokine production, activation, cell function and morphological structure. The present review aimed to propose novel diagnostic markers, at both the cellular and molecular level, which would be of great significance for the timely diagnosis of the disease. According to this aim, the characteristic changes of HSCs during HCV infection were reviewed in the present article.
Collapse
Affiliation(s)
- Wei Wang
- Department of Blood Transfusion Medicine, School of Medicine, Jinling Hospital, Nanjing University, Nanjing, Jiangsu 210002, P.R. China
| | - Xuelian Huang
- Department of Blood Transfusion Medicine, School of Medicine, Jinling Hospital, Nanjing University, Nanjing, Jiangsu 210002, P.R. China
| | - Xuzhou Fan
- Department of Blood Transfusion Medicine, School of Medicine, Jinling Hospital, Nanjing University, Nanjing, Jiangsu 210002, P.R. China
| | - Jingmei Yan
- Department of Blood Transfusion Medicine, School of Medicine, Jinling Hospital, Nanjing University, Nanjing, Jiangsu 210002, P.R. China
| | - Jianfeng Luan
- Department of Blood Transfusion Medicine, School of Medicine, Jinling Hospital, Nanjing University, Nanjing, Jiangsu 210002, P.R. China
| |
Collapse
|
|
27
|
Huang E, Peng N, Xiao F, Hu D, Wang X, Lu L. The Roles of Immune Cells in the Pathogenesis of Fibrosis. Int J Mol Sci 2020; 21:E5203. [PMID: 32708044 PMCID: PMC7432671 DOI: 10.3390/ijms21155203] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 07/19/2020] [Accepted: 07/21/2020] [Indexed: 12/15/2022] Open
Abstract
Tissue injury and inflammatory response trigger the development of fibrosis in various diseases. It has been recognized that both innate and adaptive immune cells are important players with multifaceted functions in fibrogenesis. The activated immune cells produce various cytokines, modulate the differentiation and functions of myofibroblasts via diverse molecular mechanisms, and regulate fibrotic development. The immune cells exhibit differential functions during different stages of fibrotic diseases. In this review, we summarized recent advances in understanding the roles of immune cells in regulating fibrotic development and immune-based therapies in different disorders and discuss the underlying molecular mechanisms with a focus on mTOR and JAK-STAT signaling pathways.
Collapse
Affiliation(s)
- Enyu Huang
- Department of Pathology and Shenzhen Institute of Research and Innovation, The University of Hong Kong, Hong Kong, China; (E.H.); (F.X.)
| | - Na Peng
- Department of Rheumatology and Immunology, the Second People’s Hospital of Three Gorges University, Yichang 443000, China; (N.P.); (D.H.)
| | - Fan Xiao
- Department of Pathology and Shenzhen Institute of Research and Innovation, The University of Hong Kong, Hong Kong, China; (E.H.); (F.X.)
| | - Dajun Hu
- Department of Rheumatology and Immunology, the Second People’s Hospital of Three Gorges University, Yichang 443000, China; (N.P.); (D.H.)
| | - Xiaohui Wang
- Department of Pathology and Shenzhen Institute of Research and Innovation, The University of Hong Kong, Hong Kong, China; (E.H.); (F.X.)
| | - Liwei Lu
- Department of Pathology and Shenzhen Institute of Research and Innovation, The University of Hong Kong, Hong Kong, China; (E.H.); (F.X.)
| |
Collapse
|
|
28
|
Zhang K, Liu Y, Yang X, Sun H, Shu X, Zhang Y, Cao H, Wu M, Liu N, Zou Y, Xu Q, Li G. HBV promotes the recruitment of IL-17 secreting T cells via chemokines CCL22 and CCL17. Liver Int 2020; 40:1327-1338. [PMID: 32187823 DOI: 10.1111/liv.14438] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2019] [Revised: 02/29/2020] [Accepted: 03/03/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIMS Little is known about the mechanisms of IL-17 secreting T cells accumulation in HBV-transfected livers. Here, we investigated the role of the chemokines CCL17, CCL20 and CCL22 in this process. METHODS Peripheral blood and liver tissues were obtained from 30 chronic hepatitis B (CHB) patients and 15 healthy volunteers and were evaluated by flow cytometric analysis and immunohistochemistry. Chemokine production by monocyte-derived dendritic cells (MoDCs) cocultured with HBV-transfected or untransfected Huh7 cells was measured by quantitative real-time PCR and enzyme-linked immunosorbent assay. The chemotactic activity of the culture supernatants was also tested. RESULTS The proportions of IL-17 secreting CD4 (Th17) and CD8 (Tc17) T cells were both increased in liver and peripheral blood mononuclear cells of CHB patients compared to those in HVs. CHB patients showed higher intrahepatic levels of CCL17 mRNA, CCL22 mRNA, CCR6 mRNA and CCR4 mRNA than HVs. The expression of CCR6 and CCR4 on the surface of Th17 and Tc17 cells in CHB patients was also significantly higher than that in HVs. Significant correlations existed between the CCR4/CCR6 levels and both the alanine transaminase levels and HBV DNA loads. Contact between MoDCs and pBlue-HBV-transfected Huh7 cells induced the expression of CCL17 and CCL22 dependent on the dose of HBV DNA. However, CCL20 expression was lower in CHB patients than in HVs. Transwell experiments showed that upregulation of CCL17 and CCL22 enhanced the migration of IL-17 secreting T cells. CONCLUSIONS Contact of HBV-transfected cells with MoDCs induces CCL17 and CCL22 chemokine production, which may favour the recruitment of Th17 and Tc17 cells to liver tissue in CHB. Our results reveal the mechanism of IL-17 secreting T cells recruitment to liver tissue and thus provide new immunotherapy targets for CHB patients.
Collapse
Affiliation(s)
- Ka Zhang
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, P. R. China
| | - Yanqiong Liu
- Department of Infectious Diseases, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, P. R. China
| | - Xiaoan Yang
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, P. R. China
| | - Haixia Sun
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, P. R. China
| | - Xin Shu
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, P. R. China
| | - Yeqiong Zhang
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, P. R. China
| | - Hong Cao
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, P. R. China
| | - Mengdi Wu
- General Practice Center, Nanhai Hospital, Southern Medical University, Foshan, P. R. China
| | - Nan Liu
- General Practice Center, Nanhai Hospital, Southern Medical University, Foshan, P. R. China
| | - Yong Zou
- Department of Blood Transfusion, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, P. R. China
| | - Qihuan Xu
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, P. R. China
| | - Gang Li
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, P. R. China
| |
Collapse
|
|
29
|
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.
Collapse
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
| |
Collapse
|
|
30
|
Roehlen N, Crouchet E, Baumert TF. Liver Fibrosis: Mechanistic Concepts and Therapeutic Perspectives. Cells 2020; 9:cells9040875. [PMID: 32260126 PMCID: PMC7226751 DOI: 10.3390/cells9040875] [Citation(s) in RCA: 700] [Impact Index Per Article: 140.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Revised: 03/28/2020] [Accepted: 04/01/2020] [Indexed: 02/06/2023] Open
Abstract
Liver fibrosis due to viral or metabolic chronic liver diseases is a major challenge of global health. Correlating with liver disease progression, fibrosis is a key factor for liver disease outcome and risk of hepatocellular carcinoma (HCC). Despite different mechanism of primary liver injury and disease-specific cell responses, the progression of fibrotic liver disease follows shared patterns across the main liver disease etiologies. Scientific discoveries within the last decade have transformed the understanding of the mechanisms of liver fibrosis. Removal or elimination of the causative agent such as control or cure of viral infection has shown that liver fibrosis is reversible. However, reversal often occurs too slowly or too infrequent to avoid life-threatening complications particularly in advanced fibrosis. Thus, there is a huge unmet medical need for anti-fibrotic therapies to prevent liver disease progression and HCC development. However, while many anti-fibrotic candidate agents have shown robust effects in experimental animal models, their anti-fibrotic effects in clinical trials have been limited or absent. Thus, no approved therapy exists for liver fibrosis. In this review we summarize cellular drivers and molecular mechanisms of fibrogenesis in chronic liver diseases and discuss their impact for the development of urgently needed anti-fibrotic therapies.
Collapse
Affiliation(s)
- Natascha Roehlen
- Université de Strasbourg, 67000 Strasbourg, France; (N.R.); (E.C.)
- Institut de Recherche sur les Maladies Virales et Hépatiques U1110, 67000 Strasbourg, France
| | - Emilie Crouchet
- Université de Strasbourg, 67000 Strasbourg, France; (N.R.); (E.C.)
- Institut de Recherche sur les Maladies Virales et Hépatiques U1110, 67000 Strasbourg, France
| | - Thomas F. Baumert
- Université de Strasbourg, 67000 Strasbourg, France; (N.R.); (E.C.)
- Institut de Recherche sur les Maladies Virales et Hépatiques U1110, 67000 Strasbourg, France
- Pôle Hepato-digestif, Institut Hopitalo-Universitaire, Hôpitaux Universitaires de Strasbourg, 67000 Strasbourg, France
- Correspondence: ; Tel.: +33-366853703
| |
Collapse
|
|
31
|
Wan Z, Zhou Z, Liu Y, Lai Y, Luo Y, Peng X, Zou W. Regulatory T cells and T helper 17 cells in viral infection. Scand J Immunol 2020; 91:e12873. [PMID: 32090360 DOI: 10.1111/sji.12873] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2019] [Revised: 02/10/2020] [Accepted: 02/20/2020] [Indexed: 12/16/2022]
Abstract
CD4+ T cells are the central element of the adaptive immune responses and protect the body from a variety of pathogens. Starting from naive cells, CD4+ T cells can differentiate into various effector cell subsets with specialized functions including T helper (Th) 1, Th2, Th17, regulatory T (Treg) and T follicular helper (Tfh) cells. Among them, Tregs and Th17 cells show a strong plasticity allowing the functional adaptation to various physiological and pathological environments during immune responses. Although they are derived from the same precursor cells and their differentiation pathways are interrelated, the terminally differentiated cells have totally opposite functions. Studies have shown that Tregs and Th17 cells have rather complex interplays in viral infection: Th17 cells may contribute to immune activation and disease progression while Tregs may inhibit this process and play a key role in the maintenance of immune homoeostasis, possibly at the cost of compromised viral control. In this review, we take respiratory syncytial virus (RSV), hepatitis B virus (HBV)/hepatitis C virus (HCV) and human immunodeficiency virus (HIV) infections as examples to discuss these interplays and their impacts on disease progression in viral infection.
Collapse
Affiliation(s)
- Zhikai Wan
- Medical College of Nanchang University, Nanchang, China
| | - Zhifeng Zhou
- Medical College of Nanchang University, Nanchang, China
| | - Yao Liu
- Medical College of Nanchang University, Nanchang, China
| | - Yuhan Lai
- Medical College of Nanchang University, Nanchang, China
| | - Yuan Luo
- Medical College of Nanchang University, Nanchang, China
| | - Xiaoping Peng
- Department of Cardiology, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Wei Zou
- Department of Infectious Diseases, the First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| |
Collapse
|
|
32
|
Li S, Huang N, Dang X, Li L, Li Z, Zhang C, Jiang A, Kong G, Ji F, Yang J, Li Z. A Comparison of Splenic Pathologic Change and Immune Function in HBV-Related Portal Hypertension and Chinese Budd-Chiari Syndrome Patients with Hypersplenism. Viral Immunol 2020; 33:112-121. [PMID: 32101101 DOI: 10.1089/vim.2019.0146] [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] [Indexed: 11/13/2022] Open
Abstract
The difference of splenic pathologic alterations and immune function changes in portal hypertension (PHT) with different etiology is unclear. We aimed to investigate the differences between the hypersplenic patients with hepatitis B virus (HBV)-related PHT and Budd-Chiari syndrome (B-CS). A total of 93 patients with hypersplenism due to Chinese primary B-CS (B-CS group), 105 patients with hypersplenism due to HBV-related cirrhosis (HBV/PHT group), and 31 healthy people (control group) were included in this study retrospectively. The peripheral bloods and paraffin sections of the spleen from part of patients were analyzed by flow cytometry and immunohistochemistry. Hypersplenism and PHT were more serious in HBV/PHT group than in B-CS group. In the peripheral blood, the percentages of regulatory T cell (15.1% vs. 8.1% vs. 2.2%, p = 0.0021) and myeloid-derived suppressive cells (2.8% vs. 0.8% vs. 0.9%, p = 0.009) were higher, but CD4+ T and CD8+ T cells were lower in HBV/PHT group compared with B-CS and control groups. In spleen, the percentages of CD4+ T and CD8+ T cells were lower, but CD68+ macrophages were higher in HBV/PHT group than in B-CS group. Moreover, CD86, inducible nitric oxide synthase, Toll-like receptor 4, and tumor necrosis factor-α expression in the spleen, as well as the plasma lipopolysaccharide (LPS) level (677.7 vs. 311.1 vs. 222.1 ng/mL, p = 0.0022), were significantly higher in HBV/PHT group than in B-CS and control groups. The HBV/PHT group showed more severe immunosuppression and immune dysfunction and more substantial hypersplenism and splenic phagocytosis than B-CS group.
Collapse
Affiliation(s)
- Suxin Li
- National and Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Shaanxi Provincial Clinical Research Center for Hepatic and Splenic Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, China
| | - Na Huang
- National and Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Shaanxi Provincial Clinical Research Center for Hepatic and Splenic Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Xiaowei Dang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, China
| | - Liang Li
- National and Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Shaanxi Provincial Clinical Research Center for Hepatic and Splenic Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Zhenzhen Li
- National and Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Shaanxi Provincial Clinical Research Center for Hepatic and Splenic Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Chen Zhang
- National and Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Shaanxi Provincial Clinical Research Center for Hepatic and Splenic Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - An Jiang
- National and Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Shaanxi Provincial Clinical Research Center for Hepatic and Splenic Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Guangyao Kong
- National and Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Shaanxi Provincial Clinical Research Center for Hepatic and Splenic Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education of China, Xi'an, China
| | - Fanpu Ji
- National and Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Shaanxi Provincial Clinical Research Center for Hepatic and Splenic Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Department of Infectious Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education of China, Xi'an, China
| | - Jun Yang
- National and Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Department of Pathology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Zongfang Li
- National and Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Shaanxi Provincial Clinical Research Center for Hepatic and Splenic Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education of China, Xi'an, China
| |
Collapse
|
|
33
|
Keenan BP, Fong L, Kelley RK. Immunotherapy in hepatocellular carcinoma: the complex interface between inflammation, fibrosis, and the immune response. J Immunother Cancer 2019; 7:267. [PMID: 31627733 PMCID: PMC6798343 DOI: 10.1186/s40425-019-0749-z] [Citation(s) in RCA: 152] [Impact Index Per Article: 25.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2019] [Accepted: 09/20/2019] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer deaths worldwide and confers a poor prognosis. Beyond standard systemic therapy with multikinase inhibitors, recent studies demonstrate the potential for robust and durable responses from immune checkpoint inhibition in subsets of HCC patients across disease etiologies. The majority of HCC arises in the context of chronic inflammation and from within a fibrotic liver, with many cases associated with hepatitis virus infections, toxins, and fatty liver disease. Many patients also have concomitant cirrhosis which is associated with both local and systemic immune deficiency. Furthermore, the liver is an immunologic organ in itself, which may enhance or suppress the immune response to cancer arising within it. Here, we explore the immunobiology of the liver from its native state to chronic inflammation, fibrosis, cirrhosis and then to cancer, and summarize how this unique microenvironment may affect the response to immunotherapy.
Collapse
Affiliation(s)
- Bridget P Keenan
- Division of Hematology/Oncology, Department of Medicine, University of California San Francisco, Room M1286, 505 Parnassus Ave., San Francisco, CA, 94143, USA. .,Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA.
| | - Lawrence Fong
- Division of Hematology/Oncology, Department of Medicine, University of California San Francisco, Room M1286, 505 Parnassus Ave., San Francisco, CA, 94143, USA.,Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA
| | - Robin K Kelley
- Division of Hematology/Oncology, Department of Medicine, University of California San Francisco, Room M1286, 505 Parnassus Ave., San Francisco, CA, 94143, USA.,Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA
| |
Collapse
|
|
34
|
Beneficial and Deleterious Effects of Female Sex Hormones, Oral Contraceptives, and Phytoestrogens by Immunomodulation on the Liver. Int J Mol Sci 2019; 20:ijms20194694. [PMID: 31546715 PMCID: PMC6801544 DOI: 10.3390/ijms20194694] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2019] [Revised: 09/13/2019] [Accepted: 09/20/2019] [Indexed: 12/11/2022] Open
Abstract
The liver is considered the laboratory of the human body because of its many metabolic processes. It accomplishes diverse activities as a mixed gland and is in continuous cross-talk with the endocrine system. Not only do hormones from the gastrointestinal tract that participate in digestion regulate the liver functions, but the sex hormones also exert a strong influence on this sexually dimorphic organ, via their receptors expressed in liver, in both health and disease. Besides, the liver modifies the actions of sex hormones through their metabolism and transport proteins. Given the anatomical position and physiological importance of liver, this organ is evidenced as an immune vigilante that mediates the systemic immune response, and, in turn, the immune system regulates the hepatic functions. Such feedback is performed by cytokines. Pro-inflammatory and anti-inflammatory cytokines are strongly involved in hepatic homeostasis and in pathological states; indeed, female sex hormones, oral contraceptives, and phytoestrogens have immunomodulatory effects in the liver and the whole organism. To analyze the complex and interesting beneficial or deleterious effects of these drugs by their immunomodulatory actions in the liver can provide the basis for either their pharmacological use in therapeutic treatments or to avoid their intake in some diseases.
Collapse
|
|
35
|
Chen Y, Tian Z. HBV-Induced Immune Imbalance in the Development of HCC. Front Immunol 2019; 10:2048. [PMID: 31507621 PMCID: PMC6718466 DOI: 10.3389/fimmu.2019.02048] [Citation(s) in RCA: 180] [Impact Index Per Article: 30.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2019] [Accepted: 08/13/2019] [Indexed: 12/12/2022] Open
Abstract
Chronic hepatitis B virus (HBV) infection is one of the high-risk factors for human HCC. Despite the integration of virus DNA and the oncoprotein HBx, chronic necroinflammation and hepatocellular regeneration account for hepatocarcinogenesis. As a non-cytopathic virus, HBV is extensively recognized to mediate chronic liver damage through abnormal immune attack. However, the mechanisms driving HBV infection to HCC are poorly understood. During chronic HBV infection in humans, the adaptive immunity changes from immune tolerance to progressive immune activation, inactivation, reactivation and exhaustion, all of which may be the immune pathogenic factors for the development of HCC. Recently, the immunopathogenic mechanisms were described in mouse HBV-induced HCC models, which is absolutely dependent on the presence of HBV-specific T cell response and NK cell-derived IFN-γ, findings which are consistent with the observations from CHB and HCC patients. In this review, we summarize recent research progression on the HBV-specific CD8+ T cells, and also CD4+ T cells, B cells and non-specific immune cells and molecules underlying chronic HBV infection and eventual HCC development to demonstrate the pathogenesis of HBV-induced immune imbalance. Based on the progression, we discussed the potential of immune-based therapies and their challenges in the treatment of HBV-related HCC, including the checkpoint inhibition, genetically modified T cell transfer, therapeutic vaccines and metabolic modulation.
Collapse
Affiliation(s)
- Yongyan Chen
- Hefei National Laboratory for Physical Sciences at Microscale, The CAS Key Laboratory of Innate Immunity and Chronic Disease, Division of Molecular Medicine, School of Life Sciences, University of Science and Technology of China, Hefei, China.,Institute of Immunology, University of Science and Technology of China, Hefei, China
| | - Zhigang Tian
- Hefei National Laboratory for Physical Sciences at Microscale, The CAS Key Laboratory of Innate Immunity and Chronic Disease, Division of Molecular Medicine, School of Life Sciences, University of Science and Technology of China, Hefei, China.,Institute of Immunology, University of Science and Technology of China, Hefei, China
| |
Collapse
|
|
36
|
Loh Z, Fitzsimmons RL, Reid RC, Ramnath D, Clouston A, Gupta PK, Irvine KM, Powell EE, Schroder K, Stow JL, Sweet MJ, Fairlie DP, Iyer A. Inhibitors of class I histone deacetylases attenuate thioacetamide-induced liver fibrosis in mice by suppressing hepatic type 2 inflammation. Br J Pharmacol 2019; 176:3775-3790. [PMID: 31236923 DOI: 10.1111/bph.14768] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2018] [Revised: 05/09/2019] [Accepted: 06/04/2019] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND AND PURPOSE Chronic liver diseases feature excessive collagen and matrix protein deposition or crosslinking that characterises fibrosis, leads to scar tissue, and disrupts liver functions. There is no effective treatment. This study investigated whether treatment with selective histone deacetylase (HDAC) inhibitors might specifically reduce type 2 inflammation in the injured liver, thereby attenuating fibrogenesis in mice. EXPERIMENTAL APPROACH Thioacetamide (TAA) was used to induce hepatic inflammation, fibrosis, and liver damage in female C57BL/6 mice, similar to the clinical features of chronic human liver disease. We used eight inhibitors of different human HDAC enzymes to probe histological (IHC and TUNEL), biochemical and immunological changes (flow cytometry, qPCR, Legendplex, and ELISA) in pathology, fibrosis, hepatic immune cell flux, and inflammatory cytokine expression. KEY RESULTS Inhibitors of class I, but not class II, HDAC enzymes potently suppressed chronic hepatic inflammation and fibrosis in mice, attenuating accumulation and activation of IL-33-dependent, but not IL-25-dependent, group 2 innate lymphoid cells (ILC2) and inhibiting type 2 inflammation that drives hepatic stellate cells to secrete excessive collagen and matrix proteins. CONCLUSIONS AND IMPLICATIONS The results show that potent and selective inhibitors of class I only HDAC enzymes profoundly inhibit hepatocyte death and type 2 inflammation to prevent TAA-induced liver fibrosis in mice. The specific HDAC enzymes identified here may be key promoters of inflammation in chronic liver fibrosis.
Collapse
Affiliation(s)
- Zhixuan Loh
- Centre for Inflammation and Disease Research, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia.,Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia
| | - Rebecca L Fitzsimmons
- Centre for Inflammation and Disease Research, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia.,Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia
| | - Robert C Reid
- Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia
| | - Divya Ramnath
- Centre for Inflammation and Disease Research, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia
| | - Andrew Clouston
- Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia
| | - Praveer K Gupta
- Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia
| | - Katharine M Irvine
- Mater Research, The University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia
| | - Elizabeth E Powell
- Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia
| | - Kate Schroder
- Centre for Inflammation and Disease Research, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia
| | - Jennifer L Stow
- Centre for Inflammation and Disease Research, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia
| | - Matthew J Sweet
- Centre for Inflammation and Disease Research, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia
| | - David P Fairlie
- Centre for Inflammation and Disease Research, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia.,Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia
| | - Abishek Iyer
- Centre for Inflammation and Disease Research, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia.,Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia
| |
Collapse
|
|
37
|
Li TY, Yang Y, Zhou G, Tu ZK. Immune suppression in chronic hepatitis B infection associated liver disease: A review. World J Gastroenterol 2019; 25:3527-3537. [PMID: 31367154 PMCID: PMC6658392 DOI: 10.3748/wjg.v25.i27.3527] [Citation(s) in RCA: 100] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2019] [Revised: 04/29/2019] [Accepted: 06/01/2019] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus (HBV) infection is one the leading risk factors for chronic hepatitis, liver fibrosis, cirrhosis and hepatocellular cancer (HCC), which are a major global health problem. A large number of clinical studies have shown that chronic HBV persistent infection causes the dysfunction of innate and adaptive immune response involving monocytes/macrophages, dendritic cells, natural killer (NK) cells, T cells. Among these immune cells, cell subsets with suppressive features have been recognized such as myeloid derived suppressive cells(MDSC), NK-reg, T-reg, which represent a critical regulatory system during liver fibrogenesis or tumourigenesis. However, the mechanisms that link HBV-induced immune dysfunction and HBV-related liver diseases are not understood. In this review we summarize the recent studies on innate and adaptive immune cell dysfunction in chronic HBV infection, liver fibrosis, cirrhosis, and HCC, and further discuss the potential mechanism of HBV-induced immunosuppressive cascade in HBV infection and consequences. It is hoped that this article will help ongoing research about the pathogenesis of HBV-related hepatic fibrosis and HBV-related HCC.
Collapse
Affiliation(s)
- Tian-Yang Li
- Infectious Disease, Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510000, Guangdong Province, China
| | - Yang Yang
- Institute of Liver diseases, the First Hospital of Jilin University, Changchun 130061, Jilin Province, China
| | - Guo Zhou
- Infectious Disease, Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510000, Guangdong Province, China
| | - Zheng-Kun Tu
- Infectious Disease, Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510000, Guangdong Province, China
- Institute of Liver diseases, the First Hospital of Jilin University, Changchun 130061, Jilin Province, China
| |
Collapse
|
|
38
|
Lv Y, Wang X. Interleukin-37 Inhibits the Imbalance Between T Helper 17 Cells and Regulatory T Cells in Hand, Foot, and Mouth Disease. J Interferon Cytokine Res 2019; 39:421-427. [PMID: 31090483 DOI: 10.1089/jir.2019.0005] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
The aim of this study was to explore the role of interleukin-37 (IL-37) in imbalance of T helper (Th)17/regulatory T cells (Tregs) in hand, foot, and mouth disease (HFMD). The proportions of CD4+ IL-17A+ Th17 cells and CD4+ CD25+Foxp3+ Tregs in peripheral blood or peripheral blood mononuclear cells (PBMCs) from HFMD patients and healthy controls were measured by fluorescence activated cell sorter. The level of IL-37, IL-10, IL-17A, IL-23, and transforming growth factor β1 (TGF-β1) in serum or PBMCs of HFMD patients and control subjects were detected using enzyme-linked immunosorbent assay. Results showed that Th17 cells proportion and IL-17A and IL-23 levels were highly increased, whereas Tregs proportion and IL-10 and TGF-β1 levels were significantly decreased in HFMD patients. Moreover, IL-37 stimulation elevated Tregs proportion but reduced Th17 cell proportion in subjects with HFMD. On the contrary, we found methylprednisolone pulse therapy/methylprednisolone combinated with intravenous gamma globulin inhibits Th17/Treg imbalance through upregulation of IL-37 in HFMD. In conclusion, IL-37 inhibits the imbalance of Th17/Tregs in HFMD.
Collapse
Affiliation(s)
- Yong Lv
- Department of Pediatric, The First Affiliated Hospital of University of Science and Technology of China (USTC), Hefei, China
| | - Xuesong Wang
- Department of Pediatric, The First Affiliated Hospital of University of Science and Technology of China (USTC), Hefei, China
| |
Collapse
|
|
39
|
Yang L, Jia S, Shao X, Liu S, Zhang Q, Song J, Wang W, Jin Z. Interleukin-35 modulates the balance between viral specific CD4 +CD25 +CD127 dim/- regulatory T cells and T helper 17 cells in chronic hepatitis B virus infection. Virol J 2019; 16:48. [PMID: 30992023 PMCID: PMC6469219 DOI: 10.1186/s12985-019-1158-0] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2019] [Accepted: 04/03/2019] [Indexed: 12/13/2022] Open
Abstract
Background Interleukin (IL)-35 regulates imbalance between regulatory T cells (Tregs) and T helper (Th) 17 cells, leading to an important modulator in autoimmune disorder, cancer, and infectious diseases. Our previous study revealed an immunosuppressive activity of IL-35 in chronic hepatitis B virus (HBV) infection. Thus, the aim of the current study was to investigate the role of regulatory function of IL-35 to viral specific Tregs/Th17 cells balance in chronic HBV infection. Methods A total of 44 HLA-A2 restricted chronic HBV infected patients, including 21 of chronic hepatitis B (CHB) and 23 of asymptomatic HBV carriers (ASC) were enrolled. Purified CD4+ T cells or CD4+CD25+CD127dim/− Tregs were stimulated with recombinant IL-35. HBV core antigen specific Tregs and Th17 cells were determined by flow cytometry. FoxP3 and RORγt mRNA was measured by real-time PCR. Cytokines production (IL-10 and IL-17) was investigated by ELISA. Results Peripheral viral specific Tregs was comparable between CHB and ASC. However, increased percentage of viral specific Th17 cells was found in CHB, leading to the reduction of Tregs/Th17 ratio in CHB patients. IL-35 stimulation elevated viral specific Tregs, but not Th17 cells frequency, in both CHB and ASC, resulting in the elevation of Tregs/Th17 ratio in both groups. This process was accompanied by increased expression of FoxP3 mRNA and IL-10 production, and decreased IL-17 secretion and STAT3 phosphorylation in purified CD4+ T cells. Moreover, IL-35 stimulation inhibited viral specific Th17-like phenotype differentiation from Tregs in CHB patients. Effective anti-HBV therapy did not affect viral specific Tregs/Th17 cells frequency or IL-35 expression in CHB patients, however, reduced responsiveness of CD4+ T cells or Tregs to IL-35 stimulation in vitro. Conclusion Our findings indicated that IL-35 regulation to viral specific Tregs/Th17 balance may contribute to viral persistence in chronic HBV infection.
Collapse
Affiliation(s)
- Lanlan Yang
- Department of Hepatopancreatobiliary Medicine, The Second Hospital, Jilin University, No. 218 Ziqiang Street, Nanguan District, Changchun, 130041, Jilin Province, China
| | - Shengnan Jia
- Department of Hepatopancreatobiliary Medicine, The Second Hospital, Jilin University, No. 218 Ziqiang Street, Nanguan District, Changchun, 130041, Jilin Province, China
| | - Xue Shao
- Department of Hepatopancreatobiliary Medicine, The Second Hospital, Jilin University, No. 218 Ziqiang Street, Nanguan District, Changchun, 130041, Jilin Province, China
| | - Siqi Liu
- Department of Hepatopancreatobiliary Medicine, The Second Hospital, Jilin University, No. 218 Ziqiang Street, Nanguan District, Changchun, 130041, Jilin Province, China
| | - Qian Zhang
- Department of Hepatopancreatobiliary Medicine, The Second Hospital, Jilin University, No. 218 Ziqiang Street, Nanguan District, Changchun, 130041, Jilin Province, China
| | - Jie Song
- Department of Hepatopancreatobiliary Medicine, The Second Hospital, Jilin University, No. 218 Ziqiang Street, Nanguan District, Changchun, 130041, Jilin Province, China
| | - Wudong Wang
- Department of Hepatopancreatobiliary Medicine, The Second Hospital, Jilin University, No. 218 Ziqiang Street, Nanguan District, Changchun, 130041, Jilin Province, China
| | - Zhenjing Jin
- Department of Hepatopancreatobiliary Medicine, The Second Hospital, Jilin University, No. 218 Ziqiang Street, Nanguan District, Changchun, 130041, Jilin Province, China.
| |
Collapse
|
|
40
|
Zhang H, Jiang Z, Zhang L. Dual effect of T helper cell 17 (Th17) and regulatory T cell (Treg) in liver pathological process: From occurrence to end stage of disease. Int Immunopharmacol 2019; 69:50-59. [PMID: 30669025 DOI: 10.1016/j.intimp.2019.01.005] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2018] [Revised: 01/02/2019] [Accepted: 01/04/2019] [Indexed: 02/06/2023]
Abstract
Liver disease is a complicated pathological status with acute or chronic progressions, causing a series of damages to liver and massive burden to public health and society. Th17 and Treg, two subsets of CD4+ T helper cells, seem to keep a subtle balance in the maintenance of organic immune homeostasis including liver. The dysfunction of Th17/Treg balance in liver has been proved associated with hepatic injury and disease. Herein, we summarized the research advance of Th17 and Treg cells in different phenotypes of liver diseases in the past decade. It is known to all that hepatic diseases start from stimulations or infections like virus, autoimmune, alcohol and so on in the early stage, which would cause inflammation. With the disease consistently existed, severe outcomes like cirrhosis and hepatocellular carcinoma appear finally. In conclusion, it is found that Th17 and Treg cells serve as an important role in the immune response imbalance of liver diseases from the beginning to the end stage. However, the effect of these two subsets of CD4+ T helper cells is not a stereotype. Pathological role which exacerbates the disease and protective character which inhibits damage to liver are co-existed in the effect of Th17 and Treg cells. Still, more studies should be carried out to enrich the understandings of liver disease and Th17/Treg immune balance in the future.
Collapse
Affiliation(s)
- Haoran Zhang
- Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, China
| | - Zhenzhou Jiang
- Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, China; Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing 210009, China.
| | - Luyong Zhang
- Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, China; Center for Drug Screening and Pharmacodynamics Evaluation, School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China.
| |
Collapse
|
|
41
|
Xu Y, Tang X, Yang M, Zhang S, Li S, Chen Y, Liu M, Guo Y, Lu M. Interleukin 10 Gene-Modified Bone Marrow-Derived Dendritic Cells Attenuate Liver Fibrosis in Mice by Inducing Regulatory T Cells and Inhibiting the TGF- β/Smad Signaling Pathway. Mediators Inflamm 2019; 2019:4652596. [PMID: 30800002 PMCID: PMC6360045 DOI: 10.1155/2019/4652596] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2018] [Revised: 09/14/2018] [Accepted: 11/05/2018] [Indexed: 12/30/2022] Open
Abstract
AIM To explore the therapeutic effects and mechanisms of interleukin 10 gene-modified bone marrow-derived dendritic cells (DC-IL10) on liver fibrosis. METHODS In vitro, BMDCs were transfected with lentiviral-interleukin 10-GFP (LV-IL10-GFP) at the MOI of 1 : 40. Then, the phenotype (MHCII, CD80, and CD86) and allo-stimulatory ability of DC-IL10 were identified by flow cytometry, and the levels of IL-10 and IL-12 (p70) secreted into the culture supernatants were quantified by ELISA. In vivo, DC-IL10 was injected into mice with CCl4-induced liver fibrosis through the tail vein. Lymphocytes were isolated to investigate the differentiation of T cells, and serum and liver tissue were collected for biochemical, cytokine, histopathologic, immune-histochemical, and Western blot analyzes. RESULTS In vitro, the expressions of MHCII, CD80, and CD86 in DC-IL10 were significantly suppressed, allogeneic CD4+T cells incubated with DC-IL10 showed a lower proliferative response, and the levels of IL-10 and IL-12 (p70) secreted into the DC-IL10 culture supernatants were significantly increased and decreased, respectively. In vivo, regulatory T cells (Tregs) were significantly increased, while ALT, AST, and inflammatory cytokines were significantly reduced in the DC-IL10 treatment group, and the degree of hepatic fibrosis was obviously reversed. The TGF-β/smad pathway was inhibited following DC-IL10 treatment compared to the liver fibrosis group. CONCLUSION IL-10 genetic modification of BMDCs may maintain DC in the state of tolerance and allow DC to induce T cell hyporesponsiveness or tolerance. DC-IL10 suppressed liver fibrosis by inducing Treg production and inhibiting the TGF-β/smad signaling pathway.
Collapse
Affiliation(s)
- Yejin Xu
- Department of Infectious Diseases, Jinhua Municipal Central Hospital, Jinhua, Zhejiang, China
| | - Xinyue Tang
- Department of Gastroenterology, the First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
| | - Min Yang
- Department of Infectious Disease, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou Key Laboratory of Hepatology, Institute of Hepatology, Wenzhou Medical University, Wenzhou, 325000 Zhejiang, China
| | - Shengguo Zhang
- Department of Infectious Disease, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou Key Laboratory of Hepatology, Institute of Hepatology, Wenzhou Medical University, Wenzhou, 325000 Zhejiang, China
| | - Shanshan Li
- Department of Infectious Disease, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou Key Laboratory of Hepatology, Institute of Hepatology, Wenzhou Medical University, Wenzhou, 325000 Zhejiang, China
| | - Yukai Chen
- Department of Infectious Disease, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou Key Laboratory of Hepatology, Institute of Hepatology, Wenzhou Medical University, Wenzhou, 325000 Zhejiang, China
| | - Minhui Liu
- Department of Infectious Diseases, Jinhua Municipal Central Hospital, Jinhua, Zhejiang, China
| | - Yuxiang Guo
- Department of Infectious Diseases, Jinhua Municipal Central Hospital, Jinhua, Zhejiang, China
| | - Mingqin Lu
- Department of Infectious Disease, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou Key Laboratory of Hepatology, Institute of Hepatology, Wenzhou Medical University, Wenzhou, 325000 Zhejiang, China
| |
Collapse
|
|
42
|
Sun X, Li Q. Prostaglandin EP2 receptor: Novel therapeutic target for human cancers (Review). Int J Mol Med 2018; 42:1203-1214. [PMID: 29956743 DOI: 10.3892/ijmm.2018.3744] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2018] [Accepted: 06/21/2018] [Indexed: 11/06/2022] Open
Abstract
Prostaglandin E2 (PGE2) receptor 2 subtype (EP2), which is a metabolite of arachidonic acid that binds with and regulates cellular responses to PGE2, is associated with numerous physiological and pathological events in a wide range of tissues. As a stimulatory G protein‑coupled receptor, PGE2‑induced EP2 activation can activate adenylate cyclase, leading to increased cytoplasmic cAMP levels and activation of protein kinase A. The EP2 receptor can also activate the glycogen synthase kinase 3β and β‑catenin pathways. The present study aimed to review the roles of the EP2 receptor in tumor development, including immunity, chronic inflammation, angiogenesis, metastasis and multidrug resistance. Furthermore, the involvement of the EP2 receptor signaling pathway in cancer was discussed. Understanding the role and mechanisms of action of the EP2 receptor, and its importance in targeted therapy, may help identify novel methods to improve management of numerous types of cancer.
Collapse
Affiliation(s)
- Xiaoting Sun
- Department of Medical Oncology and Cancer Institute of Integrative Medicine, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, P.R. China
| | - Qi Li
- Department of Medical Oncology and Cancer Institute of Integrative Medicine, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, P.R. China
| |
Collapse
|
|
43
|
Huang Q, Wang Y, Si C, Zhao D, Wang Y, Duan Y. Interleukin-35 Modulates the Imbalance Between Regulatory T Cells and T Helper 17 Cells in Enterovirus 71-Induced Hand, Foot, and Mouth Disease. J Interferon Cytokine Res 2017; 37:522-530. [PMID: 29172969 DOI: 10.1089/jir.2017.0080] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Interleukin (IL)-35 modulates the imbalance between regulatory T cells (Tregs) and T helper (Th) 17 cells, which played vital roles in the pathogenesis of autoimmune and infectious diseases. However, the role of Tregs/Th17 cell imbalance and the regulatory functions of IL-35 have remained largely unknown in enterovirus 71 (EV71)-induced hand, foot, and mouth disease (HFMD). In this study, a total of 47 HFMD patients (30 with mild HFMD and 17 with severe HFMD) and 13 healthy individuals were enrolled. The frequencies of CD4+CD25+CD127dim/- Tregs and CD4+IL-17+ Th17 cells, as well as IL-35 expression levels, were measured. Cellular proliferation and cytokine production was also determined in purified Tregs following recombinant IL-35 stimulation. An imbalance between Tregs and Th17 cells was observed in children with severe HFMD, which manifested as a reduction in the Tregs population and an elevation in the Th17 population. Serum IL-35 concentrations were also decreased in case of severe HFMD, which correlated with the Tregs:Th17 cell ratios. Recombinant IL-35 stimulation increased the proportion of Tregs, but downregulated that of Th17 cells. Treatment with IL-35 enhanced Tregs suppressive function and IL-35 and IL-10 expression, but reduced IL-22 secretion in both healthy individuals and those with severe HFMD. The Tregs:Th17 cell ratio was increased in the convalescent patients, however, a significant reduction in serum IL-35 was not observed. Our findings indicated that EV71 infection shifted the Tregs:Th17 cell ratio through IL-35 by downregulating inhibitory cytokine production and reducing the cell-to-cell contact inhibition of effector T cells. Regulation of IL-35 as it relates to the Tregs/Th17 balance may play a critical role in the pathogenesis of EV71-associated HFMD.
Collapse
Affiliation(s)
- Qian Huang
- 1 Department of Pediatrics, The First Affiliated Hospital of Xinxiang Medical University , Weihui, China
| | - Yanhua Wang
- 1 Department of Pediatrics, The First Affiliated Hospital of Xinxiang Medical University , Weihui, China
| | - Changyun Si
- 2 Department of Infectious Diseases, The First Affiliated Hospital of Xinxiang Medical University , Weihui, China
| | - De'an Zhao
- 1 Department of Pediatrics, The First Affiliated Hospital of Xinxiang Medical University , Weihui, China
| | - Yanping Wang
- 2 Department of Infectious Diseases, The First Affiliated Hospital of Xinxiang Medical University , Weihui, China
| | - Yuxiu Duan
- 2 Department of Infectious Diseases, The First Affiliated Hospital of Xinxiang Medical University , Weihui, China
| |
Collapse
|