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Abdelnabi MN, Hassan GS, Shoukry NH. Role of the type 3 cytokines IL-17 and IL-22 in modulating metabolic dysfunction-associated steatotic liver disease. Front Immunol 2024; 15:1437046. [PMID: 39156888 PMCID: PMC11327067 DOI: 10.3389/fimmu.2024.1437046] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2024] [Accepted: 07/12/2024] [Indexed: 08/20/2024] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) comprises a spectrum of liver diseases that span simple steatosis, metabolic dysfunction-associated steatohepatitis (MASH) and fibrosis and may progress to cirrhosis and cancer. The pathogenesis of MASLD is multifactorial and is driven by environmental, genetic, metabolic and immune factors. This review will focus on the role of the type 3 cytokines IL-17 and IL-22 in MASLD pathogenesis and progression. IL-17 and IL-22 are produced by similar adaptive and innate immune cells such as Th17 and innate lymphoid cells, respectively. IL-17-related signaling is upregulated during MASLD resulting in increased chemokines and proinflammatory cytokines in the liver microenvironment, enhanced recruitment of myeloid cells and T cells leading to exacerbation of inflammation and liver disease progression. IL-17 may also act directly by activating hepatic stellate cells resulting in increased fibrosis. In contrast, IL-22 is a pleiotropic cytokine with a dominantly protective signature in MASLD and is currently being tested as a therapeutic strategy. IL-22 also exhibits beneficial metabolic effects and abrogates MASH-related inflammation and fibrosis development via inducing the production of anti-oxidants and anti-apoptotic factors. A sex-dependent effect has been attributed to both cytokines, most importantly to IL-22 in MASLD or related conditions. Altogether, IL-17 and IL-22 are key effectors in MASLD pathogenesis and progression. We will review the role of these two cytokines and cells that produce them in the development of MASLD, their interaction with host factors driving MASLD including sexual dimorphism, and their potential therapeutic benefits.
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Affiliation(s)
- Mohamed N. Abdelnabi
- Centre de Recherche du Centre hospitalier de l’Université de Montréal (CRCHUM), Montréal, QC, Canada
- Département de microbiologie, infectiologie et immunologie, Faculté de médecine, Université de Montréal, Montréal, QC, Canada
| | - Ghada S. Hassan
- Centre de Recherche du Centre hospitalier de l’Université de Montréal (CRCHUM), Montréal, QC, Canada
| | - Naglaa H. Shoukry
- Centre de Recherche du Centre hospitalier de l’Université de Montréal (CRCHUM), Montréal, QC, Canada
- Département de médecine, Faculté de médecine, Université de Montréal, Montréal, QC, Canada
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Ogiji ED, Aboheimed N, Ross K, Voller C, Siner R, Jensen RL, Jolly CE, Carr DF. Greater mechanistic understanding of the cutaneous pathogenesis of Stevens-Johnson syndrome/toxic epidermal necrolysis can shed light on novel therapeutic strategies: a comprehensive review. Curr Opin Allergy Clin Immunol 2024; 24:218-227. [PMID: 38753537 PMCID: PMC11213502 DOI: 10.1097/aci.0000000000000993] [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] [Indexed: 05/18/2024]
Abstract
PURPOSE OF REVIEW Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) are severe cutaneous adverse drug reactions (SCARs) characterized by widespread epithelial detachment and blistering, which affects the skin and mucocutaneous membranes. To date, therapeutic interventions for SJS/TEN have focused on systematic suppression of the inflammatory response using high-dose corticosteroids or intravenous immunoglobulin G (IgG), for example. No targeted therapies for SJS/TEN currently exist. RECENT FINDINGS Though our understanding of the pathogenesis of SJS/TEN has advanced from both an immunological and dermatological perspective, this knowledge is yet to translate into the development of new targeted therapies. SUMMARY Greater mechanistic insight into SJS/TEN would potentially unlock new opportunities for identifying or repurposing targeted therapies to limit or even prevent epidermal injury and blistering.
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Affiliation(s)
- Emeka D. Ogiji
- Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, UK
- Department of Pharmacology and Therapeutics, Ebonyi State University, Abakaliki, Nigeria
| | - Nourah Aboheimed
- Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, UK
- Department of Pharmacy Practice, Princess Nourah bint Abdulrahman University, Saudi Arabia
| | - Kehinde Ross
- School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University
| | - Calum Voller
- School of Medicine, University of Liverpool, Liverpool, UK
| | - Ryan Siner
- Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, UK
| | - Rebecca L. Jensen
- Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, UK
| | - Carol E. Jolly
- Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, UK
| | - Daniel F. Carr
- Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, UK
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Zhang R, Liu H, Lin J, Ding J, You J, Geng J. AhR may be involved in Th17 cell differentiation in chronic hepatitis B. J Viral Hepat 2023; 30:939-950. [PMID: 37608767 DOI: 10.1111/jvh.13883] [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: 05/16/2023] [Revised: 07/19/2023] [Accepted: 08/09/2023] [Indexed: 08/24/2023]
Abstract
Th17 cells which are crucial for host immunity have been demonstrated to increase HBV infection. However, the mechanism of the Th17 cell increase is unknown. Hence, the mechanism of Th17 cell enhancement is important to provide a theoretical foundation for chronic hepatitis B immunotherapy. This study included 15 instances in the healthy control (HC) and 15 cohorts in the chronic hepatitis B (CHB). Their CD4+ T cells were isolated from their peripheral blood and then subjected to RNA transcriptome sequencing. Then, to identify target genes linked to Th17-cell differentiation, DEGs associated with CHB were convergent with the Th17-cell-associated genes from the KEGG database. Hub genes of DEG and target genes linked to Th17 cells were analysed for correlation. The AhR-related genes were located using the GeneMANIA database. To analyse the function of the genes, GO and KEGG pathways were employed. Protein-protein interaction network analysis employed the Metascape, STRING and Cytoscape databases. Finally, Western blotting and RT-qPCR were used to validate AhR. A total of 348 differential genes were identified in CHB patients. CytoHubba was used for screening five hub genes associated with CHB: CXCL10, RACGAP1, TPX2, FN1 and GZMA. This study aimed to determine the mechanism of elevated Th17 cells in CHB. As a result, further investigation using the convergence of DGEs and Th17 cell-related genes identified three target genes: AhR, HLA-DQA1 and HLA-DQB1, all of which were elevated in CHB. The three genes were primarily involved in immune response-related processes, according to the GO enrichment analysis. Correlation analysis of CXCL10, RACGAP1, TPX2, FN1 and GZMA genes with AhR, HLA-DQA1 and HLA-DQB1 revealed that AhR was positively associated with CXCL10 and GZMA genes, which best respond to the severity of CHB disease. Combined with the role of AhR in Th17 cell differentiation, the genes AhR was chosen for confirmation by RT-qPCR and WB in this study. The results showed that the CHB group had higher expression levels of AhR at both RT-qPCR and WB levels. Furthermore, this study's findings revealed that AhR may contribute to the development of CHB by affecting the differentiation of Th17 cells.
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Affiliation(s)
- Ruyi Zhang
- Department of Infectious Diseases and Hepatology, The First Affiliated Hospital of Kunming Medical University, Kunming, China
- Department of Infectious Diseases and Hepatology, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, China
| | - Huaie Liu
- Department of Infectious Diseases and Hepatology, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Jie Lin
- Department of Infectious Diseases and Hepatology, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Jie Ding
- The Third People's Hospital of Kunming, Kunming, China
| | - Jing You
- Department of Infectious Diseases and Hepatology, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Jiawei Geng
- Department of Infectious Diseases and Hepatology, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, China
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Jiang C, Li X, Liu C, Li G, Zheng Y, Xie L, Wu W, Feng Q. HMGB1/PTEN/PI3K axis participates in the peripheral immune cell differentiation in two representative TCM syndromes of chronic hepatitis B patients. Anat Rec (Hoboken) 2023; 306:3085-3096. [PMID: 35225421 DOI: 10.1002/ar.24899] [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: 11/30/2021] [Revised: 12/29/2021] [Accepted: 01/22/2022] [Indexed: 11/12/2022]
Abstract
Liver depression and spleen deficiency syndrome (LDSDS) and spleen-gastric damp-heat syndrome (SGDHS) are two major traditional Chinese medicine syndromes observed in chronic hepatitis B (CHB). Both syndromes exhibit significant differences in the pathogenesis and prognosis, and are closely related to the immune system. However, the underlying mechanisms are largely unknown. This study aimed to explore the immunoregulatory mechanisms of the two syndromes and promote the differentiation precision between the two syndromes. Thirty-six patients with CHB (18 LDSDS patients and 18 SGDHS patients) and 14 healthy controls were recruited into this study and blood was collected from all the subjects for testing. We studied the contents of T lymphocytes by flow cytometry and the expression levels of HMGB1/PTEN/PI3K axis proteins by enzyme-linked immunosorbent assay (Elisa). Protein-protein interaction (PPI) networks among HMGB1/PTEN/PI3K axis were constructed for functional enrichment. The correlations between T lymphocytes and proteins were analyzed by constructing multiple regression equations. The results revealed that the CD8+ T cells level in the two syndromes were lower than that in healthy controls, and the levels of Th17, Treg cells, and HMGB1, PI3K, PDK1, Akt were higher than those of the healthy controls (p < 0.05). Moreover, the levels of CD4+ T, Th17 cells, and HMGB1, PTEN, PI3K in LDSDS were higher than SGDHS (p < 0.05). PPI network indicated that HMGB1/PTEN/PI3K axis participated in T cell activation and liver pathology. Our results revealed that HMGB1/PTEN/PI3K axis may play an important role in regulating the formation of peripheral immune differences between the two syndromes. CD4+ T and Th17 are two representative immune cells that may serve as potential biological markers for LDSDS and SGDHS in CHB.
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Affiliation(s)
- Cen Jiang
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Xia Li
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Chao Liu
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Guiyu Li
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Yanfeng Zheng
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Lushuang Xie
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Wenjun Wu
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Quansheng Feng
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
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Duan M, Liu X, Yang Y, Zhang Y, Wu R, Lv Y, Lei H. Orchestrated regulation of immune inflammation with cell therapy in pediatric acute liver injury. Front Immunol 2023; 14:1194588. [PMID: 37426664 PMCID: PMC10323196 DOI: 10.3389/fimmu.2023.1194588] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Accepted: 05/26/2023] [Indexed: 07/11/2023] Open
Abstract
Acute liver injury (ALI) in children, which commonly leads to acute liver failure (ALF) with the need for liver transplantation, is a devastating life-threatening condition. As the orchestrated regulation of immune hemostasis in the liver is essential for resolving excess inflammation and promoting liver repair in a timely manner, in this study we focused on the immune inflammation and regulation with the functional involvement of both innate and adaptive immune cells in acute liver injury progression. In the context of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic, it was also important to incorporate insights from the immunological perspective for the hepatic involvement with SARS-CoV-2 infection, as well as the acute severe hepatitis of unknown origin in children since it was first reported in March 2022. Furthermore, molecular crosstalk between immune cells concerning the roles of damage-associated molecular patterns (DAMPs) in triggering immune responses through different signaling pathways plays an essential role in the process of liver injury. In addition, we also focused on DAMPs such as high mobility group box 1 (HMGB1) and cold-inducible RNA-binding protein (CIRP), as well as on macrophage mitochondrial DNA-cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway in liver injury. Our review also highlighted novel therapeutic approaches targeting molecular and cellular crosstalk and cell-based therapy, providing a future outlook for the treatment of acute liver injury.
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Affiliation(s)
- Mingyue Duan
- Department of Clinical Laboratory, The Affiliated Children’s Hospital of Xi’an Jiaotong University, Xi’an, China
- Key Laboratory of Precision Medicine to Pediatric Diseases of Shaanxi Province, Shaanxi Institute for Pediatric Diseases, The Affiliated Children’s Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Xiaoguai Liu
- Department of Infectious Diseases, The Affiliated Children’s Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Ying Yang
- Key Laboratory of Precision Medicine to Pediatric Diseases of Shaanxi Province, Shaanxi Institute for Pediatric Diseases, The Affiliated Children’s Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Yanmin Zhang
- Key Laboratory of Precision Medicine to Pediatric Diseases of Shaanxi Province, Shaanxi Institute for Pediatric Diseases, The Affiliated Children’s Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Rongqian Wu
- National Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Yi Lv
- National Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Hong Lei
- Key Laboratory of Precision Medicine to Pediatric Diseases of Shaanxi Province, Shaanxi Institute for Pediatric Diseases, The Affiliated Children’s Hospital of Xi’an Jiaotong University, Xi’an, China
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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] [Download PDF] [Figures] [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.
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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
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Efremova NA, Greshnyakova VA, Goryacheva LG. Modern concepts on pathogenetic mechanisms of liver fibrosis. JOURNAL INFECTOLOGY 2023; 15:16-24. [DOI: 10.22625/2072-6732-2023-15-1-16-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
Affiliation(s)
- N. A. Efremova
- Pediatric Research and Clinical Center for Infectious Diseases
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Singh KP, Pallett LJ, Singh H, Chen A, Otano I, Duriez M, Rombouts K, Pinzani M, Crane M, Fusai G, Avihingsanon A, Lewin SR, Maini MK. Pro-fibrogenic role of alarmin high mobility group box 1 in HIV-hepatitis B virus coinfection. AIDS 2023; 37:401-411. [PMID: 36384811 DOI: 10.1097/qad.0000000000003435] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
OBJECTIVE Liver disease is accelerated in people with HIV (PWH) with hepatitis B virus (HBV) coinfection. We hypothesized that liver fibrosis in HIV-HBV is triggered by increased hepatocyte apoptosis, microbial translocation and/or HIV/HBV viral products. DESIGN Sera from PWH with HBV coinfection versus from those with HBV only or putative mediators were used to examine the pathogenesis of liver disease in HIV-HBV. METHODS We applied sera from PWH and HBV coinfection versus HBV alone, or putative mediators (including HMGB1), to primary human hepatic stellate cells (hHSC) and examined pro-fibrogenic changes at the single cell level using flow cytometry. High mobility group box 1 (HMGB1) levels in the applied sera were assessed according to donor fibrosis stage. RESULTS Quantitative flow cytometric assessment of pro-fibrogenic and inflammatory changes at the single cell level revealed an enhanced capacity for sera from PWH with HBV coinfection to activate hHSC. This effect was recapitulated by lipopolysaccharide, HIV-gp120, hepatocyte conditioned-media and the alarmin HMGB1. Induction of hepatocyte cell death increased their pro-fibrogenic potential, an effect blocked by HMGB1 antagonist glycyrrhizic acid. Consistent with a role for this alarmin, HMGB1 levels were elevated in sera from PWH and hepatitis B coinfection compared to HBV alone and higher in those with HIV-HBV with liver fibrosis compared to those without. CONCLUSIONS Sera from PWH and HBV coinfection have an enhanced capacity to activate primary hHSC. We identified an increase in circulating HMGB1 which, in addition to HIV-gp120 and translocated microbial products, drove pro-fibrogenic changes in hHSC, as mechanisms contributing to accelerated liver disease in HIV-HBV.
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Affiliation(s)
- Kasha P Singh
- Division of Infection and Immunity, University College London, London, UK
- Department of Infectious Diseases, The University of Melbourne at the Peter Doherty Institute for Infection and Immunity
- Victorian Infectious Diseases Service, Royal Melbourne Hospital at the Peter Doherty Institute for Infection and Immunity
- Department of Infectious Diseases, Alfred Health and Monash University, Melbourne, Victoria, Australia
| | - Laura J Pallett
- Division of Infection and Immunity, University College London, London, UK
| | - Harsimran Singh
- Division of Infection and Immunity, University College London, London, UK
- Institute for Liver and Digestive Health, University College London, London, UK
| | - Antony Chen
- Division of Infection and Immunity, University College London, London, UK
| | - Itziar Otano
- Division of Infection and Immunity, University College London, London, UK
| | - Marion Duriez
- Division of Infection and Immunity, University College London, London, UK
| | - Krista Rombouts
- Institute for Liver and Digestive Health, University College London, London, UK
| | - Massimo Pinzani
- Institute for Liver and Digestive Health, University College London, London, UK
| | - Megan Crane
- Department of Infectious Diseases, The University of Melbourne at the Peter Doherty Institute for Infection and Immunity
| | - Giuseppe Fusai
- Institute for Liver and Digestive Health, University College London, London, UK
| | | | - Sharon R Lewin
- Department of Infectious Diseases, The University of Melbourne at the Peter Doherty Institute for Infection and Immunity
- Victorian Infectious Diseases Service, Royal Melbourne Hospital at the Peter Doherty Institute for Infection and Immunity
- Department of Infectious Diseases, Alfred Health and Monash University, Melbourne, Victoria, Australia
| | - Mala K Maini
- Division of Infection and Immunity, University College London, London, UK
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Wang H, Yu T, An N, Sun Y, Xu P, Han P, Zhao Y, Wang L, Ni X, Li Y, Li G, Liu Y, Peng J, Hou M, Hou Y. Enhancing regulatory T-cell function via inhibition of high mobility group box 1 protein signaling in immune thrombocytopenia. Haematologica 2023; 108:843-858. [PMID: 36263841 PMCID: PMC9973480 DOI: 10.3324/haematol.2022.281557] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Indexed: 11/09/2022] Open
Abstract
Primary immune thrombocytopenia (ITP) is the most common acquired autoimmune bleeding disorder. Abnormally increased levels of High Mobility Group Box 1 (HMGB1) protein associate with thrombocytopenia and therapeutic outcome in ITP. Previous studies proposed that a natural inhibitor of HMGB1, 18β-glycyrrhetinic acid (18β-GA), could be used for its anti-inflammatory and immune-modulatory effects, although its ability to correct immune balance in ITP is unclear. In this study, we showed that plasma HMGB1 correlated negatively with platelet counts in ITP patients, and confirmed that 18β-GA stimulated the production of regulatory T cells (Treg), restored the balance of CD4+ T-cell subsets and enhanced the suppressive function of Treg through blocking the effect on HMGB1 in patients with ITP. HMGB1 short hairpin RNA interference masked the effect of 18β-GA in Treg of ITP patients. Furthermore, we found that 18β-GA alleviated thrombocytopenia in mice with ITP. Briefly, anti-CD61 immune-sensitized splenocytes were transferred into severe combined immunodeficient mice to induce a murine model of severe ITP. The proportion of circulating Treg increased significantly, while the level of plasma HMGB1 and serum antiplatelet antibodies decreased significantly in ITP mice along 18β-GA treatment. In addition, 18β-GA reduced phagocytic activity of macrophages towards platelets both in ITP patients and ITP mice. These results indicate that 18β-GA has the potential to restore immune balance in ITP via inhibition of HMGB1 signaling. In short, this study reveals the role of HMGB1 in ITP, which may serve as a potential target for thrombocytopenia therapy.
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Affiliation(s)
- Haoyi Wang
- Department of Hematology, Qilu Hospital of Shandong University, Shandong University, Jinan, Shandong, 250012
| | - Tianshu Yu
- Department of Hematology, Qilu Hospital of Shandong University, Shandong University, Jinan, Shandong, 250012
| | - Ning An
- Laboratory of Cancer Signaling, Interdisciplinary Cluster for Applied Genoproteomics (GIGA) Stem Cells, University of Liège, CHU, Sart-Tilman, Liège, 4000 Belgium
| | - Yunqi Sun
- Department of Hematology, Qilu Hospital of Shandong University, Shandong University, Jinan, Shandong, 250012
| | - Pengcheng Xu
- Department of Hematology, Qilu Hospital of Shandong University, Shandong University, Jinan, Shandong, 250012
| | - Panpan Han
- Department of Hematology, Qilu Hospital of Shandong University, Shandong University, Jinan, Shandong, 250012
| | - Yajing Zhao
- Department of Hematology, Qilu Hospital of Shandong University, Shandong University, Jinan, Shandong, 250012
| | - Lingjun Wang
- Department of Hematology, Qilu Hospital of Shandong University, Shandong University, Jinan, Shandong, 250012
| | - Xiaofei Ni
- Department of Hematology, Qilu Hospital of Shandong University, Shandong University, Jinan, Shandong, 250012
| | - Yubin Li
- Department of Hematology, Qilu Hospital of Shandong University, Shandong University, Jinan, Shandong, 250012
| | - Guosheng Li
- Department of Hematology, Qilu Hospital of Shandong University, Shandong University, Jinan, Shandong, 250012
| | - Yanfeng Liu
- Department of Hematology, Qilu Hospital of Shandong University, Shandong University, Jinan, Shandong, 250012
| | - Jun Peng
- Department of Hematology, Qilu Hospital of Shandong University, Shandong University, Jinan, Shandong, 250012
| | - Ming Hou
- Department of Hematology, Qilu Hospital of Shandong University, Shandong University, Jinan, Shandong, 250012, China; Shandong Provincial Key Laboratory of Immunohematology, Qilu Hospital of Shandong University, Jinan.
| | - Yu Hou
- Department of Hematology, Qilu Hospital of Shandong University, Shandong University, Jinan, Shandong, 250012, China; Shandong Provincial Key Laboratory of Immunohematology, Qilu Hospital of Shandong University, Jinan.
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10
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He M, Chu T, Wang Z, Feng Y, Shi R, He M, Feng S, Lu L, Cai C, Fang F, Zhang X, Liu Y, Gao B. Inhibition of macrophages inflammasome activation via autophagic degradation of HMGB1 by EGCG ameliorates HBV-induced liver injury and fibrosis. Front Immunol 2023; 14:1147379. [PMID: 37122751 PMCID: PMC10140519 DOI: 10.3389/fimmu.2023.1147379] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Accepted: 03/29/2023] [Indexed: 05/02/2023] Open
Abstract
Background Liver fibrosis is a reversible wound-healing response that can lead to end-stage liver diseases without effective treatment, in which HBV infection is a major cause. However, the underlying mechanisms for the development of HBV-induced fibrosis remains elusive, and efficacious therapies for this disease are still lacking. In present investigation, we investigated the effect and mechanism of green tea polyphenol epigallocatechin-3-gallate (EGCG) on HBV-induced liver injury and fibrosis. Methods The effect of EGCG on liver fibrosis was examined in a recombinant cccDNA (rcccDNA) chronic HBV mouse model by immunohistochemical staining, Sirius red and Masson's trichrome staining. The functional relevance between high mobility group box 1 (HMGB1) and inflammasome activation and the role of EGCG in it were analyzed by Western blotting. The effect of EGCG on autophagic flux was determined by Western blotting and flow cytometric analysis. Results EGCG treatment efficiently was found to alleviate HBV-induced liver injury and fibrosis in a recombinant cccDNA (rcccDNA) chronic HBV mouse model, a proven suitable research platform for HBV-induced fibrosis. Mechanistically, EGCG was revealed to repress the activation of macrophage NLRP3 inflammasome, a critical trigger of HBV-induced liver fibrosis. Further study revealed that EGCG suppressed macrophage inflammasome through downregulating the level of extracellular HMGB1. Furthermore, our data demonstrated that EGCG treatment downregulated the levels of extracellular HMGB1 through activating autophagic degradation of cytoplasmic HMGB1 in hepatocytes. Accordingly, autophagy blockade was revealed to significantly reverse EGCG-mediated inhibition on extracellular HMGB1-activated macrophage inflammasome and thus suppress the therapeutic effect of EGCG on HBV-induced liver injury and fibrosis. Conclusion EGCG ameliorates HBV-induced liver injury and fibrosis via autophagic degradation of cytoplasmic HMGB1 and the subsequent suppression of macrophage inflammasome activation. These data provided a new pathogenic mechanism for HBV-induced liver fibrosis involving the extracellular HMGB1-mediated macrophage inflammasome activation, and also suggested EGCG administration as a promising therapeutic strategy for this disease.
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Affiliation(s)
- Minjing He
- Department of Immunology, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, China
| | - Tianhao Chu
- Department of Immunology, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, China
| | - Ziteng Wang
- Department of Immunology, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, China
| | - Ying Feng
- Department of Immunology, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, China
| | - Runhan Shi
- Department of Immunology, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, China
| | - Muyang He
- Department of Immunology, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, China
| | - Siheng Feng
- Department of Immunology, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, China
| | - Lin Lu
- Department of Immunology, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, China
| | - Chen Cai
- Department of Immunology, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, China
| | - Fang Fang
- Department of Dermatology, Shanghai Eighth People’s Hospital, Shanghai, China
| | - Xuemin Zhang
- Department of Trauma Emergency & Critical Care Medicine, Shanghai Fifth People’s Hospital, Fudan University, Shanghai, China
- *Correspondence: Bo Gao, ; Yi Liu, ; Xuemin Zhang,
| | - Yi Liu
- Department of Digestive Diseases, Huashan Hospital, Fudan University, Shanghai, China
- *Correspondence: Bo Gao, ; Yi Liu, ; Xuemin Zhang,
| | - Bo Gao
- Department of Immunology, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, China
- *Correspondence: Bo Gao, ; Yi Liu, ; Xuemin Zhang,
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11
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Ye Z, Huang Q, She Y, Hu Y, Wu M, Qin K, Li L, Zhang C, Zuo X, Wei A, Mao D, Ye Q. A meritorious integrated medical regimen for hepatic fibrosis and its complications via the systematic review and meta-analysis for Dahuang Zhechong pill-based therapy. Front Med (Lausanne) 2022; 9:920062. [PMID: 36314011 PMCID: PMC9616118 DOI: 10.3389/fmed.2022.920062] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Accepted: 09/20/2022] [Indexed: 11/13/2022] Open
Abstract
Background Hepatic fibrosis is a health challenge due to the absence of satisfactory therapy, especially at the cirrhosis stage. Dahuang Zhechong pill (DHZCP)-based therapy is reportedly a successful treatment for hepatic fibrosis and is even beneficial for the treatment of cirrhosis. Hence, a systematic review and clinical evidence assessment of DHZCP-based therapy should be performed, and clinical recommendations based on its efficacy for the treatment of hepatic fibrosis should be generated. With respect to potential indicators, the comparative value of the hepatic function, spleen thickness, and portal vein internal diameter should be evaluated. Materials and methods PubMed, the Excerpta Medica Database, the Cochrane Library, the Web of Science, the WanFang Database, the Chinese Scientific Journal Database, and the Chinese National Knowledge Infrastructure database were searched to identify clinical trials. Three subgroup analyses were performed based on the stage of disease, medication use, and the course of treatment. Statistical analyses were performed using Review Manager 5.4. Results A total of 18 studies including 1,494 patients were evaluated. The DHZCP-based therapy was effective in reducing the plasma levels of hyaluronic acid, and laminin, procollagen III, and IV collagen were also reduced irrespective of the hepatitis stage or the presence of hepatic cirrhosis. Abnormalities in alanine aminotransferase, aspartate aminotransferase, albumin, and total bilirubin were reversed. A 6-month course of treatment was the most beneficial DHZCP-based therapy regimen. Alanine aminotransferase improvement was more obvious in patients with cirrhosis, and alanine aminotransferase was reduced significantly in patients with hepatic cirrhosis. With respect to pharmacological mechanisms, DHZCP-based therapy could inhibit hepatic stellate cell growth and activation, reduce inflammation, and prevent extracellular matrix formation. Hepatic portal hypertension and splenomegaly were ameliorated significantly in the DHZCP-based therapy group. Conclusion Dahuang Zhechong pill-based therapy has demonstrated efficacy as a treatment for hepatic fibrosis and cirrhosis. A 6-month course of treatment is the recommended option for DHZCP-based therapy in clinical practice. The combination of DHZCP-based therapy and entecavir is a favorable treatment for hepatic cirrhosis.
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Affiliation(s)
- Zhen Ye
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Qinfeng Huang
- Department of Oncology, The First Affiliated Hospital, Guangxi University of Chinese Medicine, Nanning, China
| | - Yingqi She
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yu Hu
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Mingquan Wu
- Department of Pharmacy, Sichuan Orthopedic Hospital, Chengdu, Sichuan, China
| | - Kaihua Qin
- Health Preservation and Rehabilitation College, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Linzhen Li
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Chuantao Zhang
- Department of Respiratory Medicine, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Xiaohong Zuo
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Ailing Wei
- Department of Liver Disease, The First Affiliated Hospital, Guangxi University of Chinese Medicine, Nanning, China
| | - Dewen Mao
- Department of Liver Disease, The First Affiliated Hospital, Guangxi University of Chinese Medicine, Nanning, China
| | - Qiaobo Ye
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China,*Correspondence: Qiaobo Ye,
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12
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Zhang G, Yang P, Liu X, Liu H, Wang J, Wang J, Xiao J, Nie D, Ma L. HMGB1 is increased in patients with immune thrombocytopenia and negatively associates with Tregs. Thromb Res 2022; 213:128-136. [DOI: 10.1016/j.thromres.2022.02.021] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2021] [Revised: 02/21/2022] [Accepted: 02/23/2022] [Indexed: 12/24/2022]
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13
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Xu X, Wang J, Zhu D, Yin J, Liu J, Wu X, Yang W, Hu Q, Ren Y, Zhang Z, Zhou P, Wei Z, Zou H, Cao Y. Low-dose aspirin protects unexplained recurrent spontaneous abortion via downregulation of HMGB1 inflammation activation. Front Endocrinol (Lausanne) 2022; 13:914030. [PMID: 36465622 PMCID: PMC9712724 DOI: 10.3389/fendo.2022.914030] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Accepted: 10/28/2022] [Indexed: 11/18/2022] Open
Abstract
BACKGROUND High mobility group box protein 1 (HMGB1) is considered as a kind of sterile inflammatory mediators, which is an overexpression in patients with unexplained recurrent spontaneous abortion (URSA). Specific targeting effect of aspirin on HMGB1 has been revealed. Our previous studies have explored the application of HMGB1 as a therapeutic target of aspirin in URSA disease of mice model and human, but the dynamic process of aspirin downregulating HMGB1 concentration has not been demonstrated. METHODS From December 2018 to November 2020, women with URSA (n = 91) and control women (n = 90) with no history of recurrent abortion or adverse pregnancy were included in the Reproductive Medicine Center of the First Affiliated Hospital of Anhui Medical University. ELISA was applied to detect the concentrations of HMGB1 and IFN-γ in the peripheral blood. Thirty-one URSA patients were monitored for low-dose aspirin treatment (2 and 4 weeks), the changes of HMGB1 and IFN-γ concentrations in peripheral blood of URSA patients before and after using aspirin were compared, and pregnancy outcomes after aspirin treatment were followed up. RESULTS The levels of HMGB1 in peripheral blood were significantly higher in URSA patients compared with controls, decreasing trends of HMGB1 and IFN-γ concentrations in plasma of URSA patients were observed after treatment with low-dose aspirin continuously, and the expression of HMGB1 was positively correlated with IFN-γ. There were no birth abnormalities in the babies of the URSA patients treated with aspirin. CONCLUSIONS High levels of HMGB1 may be one of the pathogenesis of URSA. Low-dose aspirin may provide protective effect on the HMGB1-triggered URSA.
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Affiliation(s)
- Xiaofeng Xu
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei, China
- National Health Commission (NHC) Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), Hefei, China
- Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People’s Republic of China, Hefei, Anhui, China
| | - Jing Wang
- Center for Reproductive Medicine, Ma’anshan Maternal and Child Health Hospital, Ma’anshan, Anhui, China
| | - Damin Zhu
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei, China
- Anhui Province Key Laboratory of Reproductive Health and Genetics (Anhui Medical University), Hefei, Anhui, China
- Biopreservation and Artificial Organs, Anhui Provincial Engineering Research Center, Anhui Medical University, Hefei, Anhui, China
| | - Jiaqian Yin
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei, China
- Anhui Province Key Laboratory of Reproductive Health and Genetics (Anhui Medical University), Hefei, Anhui, China
- Biopreservation and Artificial Organs, Anhui Provincial Engineering Research Center, Anhui Medical University, Hefei, Anhui, China
| | - Jinxian Liu
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei, China
- Anhui Province Key Laboratory of Reproductive Health and Genetics (Anhui Medical University), Hefei, Anhui, China
- Biopreservation and Artificial Organs, Anhui Provincial Engineering Research Center, Anhui Medical University, Hefei, Anhui, China
| | - Xiao Wu
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei, China
- Anhui Province Key Laboratory of Reproductive Health and Genetics (Anhui Medical University), Hefei, Anhui, China
- Biopreservation and Artificial Organs, Anhui Provincial Engineering Research Center, Anhui Medical University, Hefei, Anhui, China
| | - Wenjuan Yang
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei, China
- Anhui Province Key Laboratory of Reproductive Health and Genetics (Anhui Medical University), Hefei, Anhui, China
- Biopreservation and Artificial Organs, Anhui Provincial Engineering Research Center, Anhui Medical University, Hefei, Anhui, China
| | - Qian Hu
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei, China
- Anhui Province Key Laboratory of Reproductive Health and Genetics (Anhui Medical University), Hefei, Anhui, China
- Biopreservation and Artificial Organs, Anhui Provincial Engineering Research Center, Anhui Medical University, Hefei, Anhui, China
| | - Yu Ren
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei, China
- Anhui Province Key Laboratory of Reproductive Health and Genetics (Anhui Medical University), Hefei, Anhui, China
- Biopreservation and Artificial Organs, Anhui Provincial Engineering Research Center, Anhui Medical University, Hefei, Anhui, China
| | - Zhiguo Zhang
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei, China
- Anhui Province Key Laboratory of Reproductive Health and Genetics (Anhui Medical University), Hefei, Anhui, China
- Biopreservation and Artificial Organs, Anhui Provincial Engineering Research Center, Anhui Medical University, Hefei, Anhui, China
| | - Ping Zhou
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei, China
- Anhui Province Key Laboratory of Reproductive Health and Genetics (Anhui Medical University), Hefei, Anhui, China
- Biopreservation and Artificial Organs, Anhui Provincial Engineering Research Center, Anhui Medical University, Hefei, Anhui, China
| | - Zhaolian Wei
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei, China
- Anhui Province Key Laboratory of Reproductive Health and Genetics (Anhui Medical University), Hefei, Anhui, China
- Biopreservation and Artificial Organs, Anhui Provincial Engineering Research Center, Anhui Medical University, Hefei, Anhui, China
| | - Huijuan Zou
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei, China
- National Health Commission (NHC) Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), Hefei, China
- Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People’s Republic of China, Hefei, Anhui, China
- *Correspondence: Yunxia Cao, ;; Huijuan Zou,
| | - Yunxia Cao
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei, China
- National Health Commission (NHC) Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), Hefei, China
- Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People’s Republic of China, Hefei, Anhui, China
- *Correspondence: Yunxia Cao, ;; Huijuan Zou,
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Li J, Cheng L, Jia H, Liu C, Wang S, Liu Y, Shen Y, Wu S, Meng F, Zheng B, Yang C, Jiang W. IFN-γ facilitates liver fibrogenesis by CD161 +CD4 + T cells through a regenerative IL-23/IL-17 axis in chronic hepatitis B virus infection. Clin Transl Immunology 2021; 10:e1353. [PMID: 34754450 PMCID: PMC8563156 DOI: 10.1002/cti2.1353] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Revised: 10/01/2021] [Accepted: 10/11/2021] [Indexed: 12/13/2022] Open
Abstract
OBJECTIVES This study aimed to determine the role of CD161+CD4+ T cells in chronic hepatitis B virus (HBV) infection. METHODS A total of 94 patients with chronic hepatitis B (CHB), 73 with liver cirrhosis (LC) and 28 healthy controls were enrolled to determine frequency, cytokine production and chemokine receptor expression of circulating CD161+CD4+ T cells. Among these, 50 CHB and 34 LC patients were followed up for a period of 52-week entecavir monotherapy to assess the association of CD161+CD4+ T cells with seroconversion of HBV e antigen (HBeAg). In addition, 15 patients with hepatocellular carcinoma (HCC) and 15 with hepatic haemangioma (HHA) were enrolled to compare the paired circulating and intrahepatic CD161+CD4+ T cells. RESULTS CD161+CD4+ T cells were found to accumulate in the circulation of HBV cohorts, which showed a significant correlation with the clinical parameters of disease progression. In addition, higher numbers of circulating CD161+CD4+ T cells were associated with an improved serological response of HBeAg to antiviral treatment. Moreover, CD161+CD4+ T cells as compared to homologous CD161-CD4+ T cells produced more pro-inflammatory cytokines including interleukin (IL)-17 and interferon (IFN)-γ and expressed higher levels of liver-homing chemokine receptors including CCR6, CXCR6 and CX3CR1. Notably, a significant enrichment of CD161+CD4+ T cell subsets co-expressing IFN-γ and IL-17 was observed in HBV-associated cirrhotic livers. During in vitro co-cultures, circulating CD161+CD4+ T cells in the chronic HBV setting exhibited prominent pro-fibrogenic effects by regulating primary hepatic stellate cells through a regenerative IFN-γ/IL-23/IL-17 axis. CONCLUSIONS In chronic HBV infection, CD161+CD4+ T cells play antiviral, pro-inflammatory and pro-fibrogenic roles.
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Affiliation(s)
- Jing Li
- Department of Gastroenterology and HepatologyTongji HospitalSchool of MedicineTongji UniversityShanghaiChina
| | - Lisha Cheng
- Department of Gastroenterology and HepatologyZhongshan HospitalFudan UniversityShanghaiChina
- Department of OncologyXiamen Branch of Zhongshan HospitalFudan UniversityShanghaiChina
| | - Haoyu Jia
- Department of Gastroenterology and HepatologyTongji HospitalSchool of MedicineTongji UniversityShanghaiChina
| | - Chun Liu
- Department of Gastroenterology and HepatologyTongji HospitalSchool of MedicineTongji UniversityShanghaiChina
| | - Siqi Wang
- Department of Gastroenterology and HepatologyZhongshan HospitalFudan UniversityShanghaiChina
- Shanghai Institute of Liver DiseaseShanghaiChina
| | - Yun Liu
- Department of Gastroenterology and HepatologyZhongshan HospitalFudan UniversityShanghaiChina
| | - Yue Shen
- Department of Gastroenterology and HepatologyZhongshan HospitalFudan UniversityShanghaiChina
- Shanghai Institute of Liver DiseaseShanghaiChina
| | - Shengdi Wu
- Department of Gastroenterology and HepatologyZhongshan HospitalFudan UniversityShanghaiChina
- Shanghai Institute of Liver DiseaseShanghaiChina
| | - Fanli Meng
- Department of HepatologyQilu HospitalShandong UniversityShandongChina
| | - Beishi Zheng
- Department of Internal MedicineWoodhull Medical CenterNew YorkNYUSA
| | - Changqing Yang
- Department of Gastroenterology and HepatologyTongji HospitalSchool of MedicineTongji UniversityShanghaiChina
| | - Wei Jiang
- Department of Gastroenterology and HepatologyZhongshan HospitalFudan UniversityShanghaiChina
- Shanghai Institute of Liver DiseaseShanghaiChina
- Department of Gastroenterology and HepatologyXiamen Branch of Zhongshan HospitalFudan UniversityShanghaiChina
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15
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Zhao Z, Feng M, Wan J, Zheng X, Teng C, Xie X, Pan W, Hu B, Huang J, Liu Z, Wu J, Cai S. Research progress of epigallocatechin-3-gallate (EGCG) on anti-pathogenic microbes and immune regulation activities. Food Funct 2021; 12:9607-9619. [PMID: 34549212 DOI: 10.1039/d1fo01352a] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
At the end of 2019, the COVID-19 virus spread worldwide, infecting millions of people. Infectious diseases induced by pathogenic microorganisms such as the influenza virus, hepatitis virus, and Mycobacterium tuberculosis are also a major threat to public health. The high mortality caused by infectious pathogenic microorganisms is due to their strong virulence, which leads to the excessive counterattack by the host immune system and severe inflammatory damage of the immune system. This paper reviews the efficacy, mechanism and related immune regulation of epigallocatechin-3-gallate (EGCG) as an anti-pathogenic microorganism drug. EGCG mainly shows both direct and indirect anti-infection effects. EGCG directly inhibits early infection by interfering with the adsorption on host cells, inhibiting virus replication and reducing bacterial biofilm formation and toxin release; EGCG indirectly inhibits infection by regulating immune inflammation and antioxidation. At the same time, we reviewed the bioavailability and safety of EGCG in vivo. At present, the bioavailability of EGCG can be improved to some extent using nanostructured drug delivery systems and molecular modification technology in combination with other drugs. This study provides a theoretical basis for the development of EGCG as an adjuvant drug for anti-pathogenic microorganisms.
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Affiliation(s)
- Zijuan Zhao
- National Research Center of Engineering Technology for Utilization of Botanical Functional Ingredients, Hunan Agricultural University, Changsha 410128, China. .,Key Laboratory of Ministry of Education for Tea Science, Hunan Agricultural University, Changsha 410128, China
| | - Meiyan Feng
- National Research Center of Engineering Technology for Utilization of Botanical Functional Ingredients, Hunan Agricultural University, Changsha 410128, China. .,Key Laboratory of Ministry of Education for Tea Science, Hunan Agricultural University, Changsha 410128, China
| | - Juan Wan
- National Research Center of Engineering Technology for Utilization of Botanical Functional Ingredients, Hunan Agricultural University, Changsha 410128, China. .,Key Laboratory of Ministry of Education for Tea Science, Hunan Agricultural University, Changsha 410128, China
| | - Xin Zheng
- National Research Center of Engineering Technology for Utilization of Botanical Functional Ingredients, Hunan Agricultural University, Changsha 410128, China. .,Key Laboratory of Ministry of Education for Tea Science, Hunan Agricultural University, Changsha 410128, China
| | - Cuiqin Teng
- Wuzhou Institute of Agricultural, Wuzhou 543003, China
| | - Xinya Xie
- National Research Center of Engineering Technology for Utilization of Botanical Functional Ingredients, Hunan Agricultural University, Changsha 410128, China. .,Key Laboratory of Ministry of Education for Tea Science, Hunan Agricultural University, Changsha 410128, China
| | - Wenjing Pan
- National Research Center of Engineering Technology for Utilization of Botanical Functional Ingredients, Hunan Agricultural University, Changsha 410128, China. .,Key Laboratory of Ministry of Education for Tea Science, Hunan Agricultural University, Changsha 410128, China
| | - Baozhu Hu
- National Research Center of Engineering Technology for Utilization of Botanical Functional Ingredients, Hunan Agricultural University, Changsha 410128, China. .,Key Laboratory of Ministry of Education for Tea Science, Hunan Agricultural University, Changsha 410128, China
| | - Jianan Huang
- National Research Center of Engineering Technology for Utilization of Botanical Functional Ingredients, Hunan Agricultural University, Changsha 410128, China. .,Key Laboratory of Ministry of Education for Tea Science, Hunan Agricultural University, Changsha 410128, China.,Co-Innovation Center of Education Ministry for Utilization of Botanical Functional Ingredients, Hunan Agricultural University, Changsha 410128, China
| | - Zhonghua Liu
- National Research Center of Engineering Technology for Utilization of Botanical Functional Ingredients, Hunan Agricultural University, Changsha 410128, China. .,Key Laboratory of Ministry of Education for Tea Science, Hunan Agricultural University, Changsha 410128, China.,Co-Innovation Center of Education Ministry for Utilization of Botanical Functional Ingredients, Hunan Agricultural University, Changsha 410128, China
| | - Jianhua Wu
- Wuzhou Institute of Agricultural, Wuzhou 543003, China
| | - Shuxian Cai
- National Research Center of Engineering Technology for Utilization of Botanical Functional Ingredients, Hunan Agricultural University, Changsha 410128, China. .,Key Laboratory of Ministry of Education for Tea Science, Hunan Agricultural University, Changsha 410128, China.,Co-Innovation Center of Education Ministry for Utilization of Botanical Functional Ingredients, Hunan Agricultural University, Changsha 410128, China
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Li L, Xia Y, Ji X, Wang H, Zhang Z, Lu P, Ding Q, Wang D, Liu M. MIG/CXCL9 exacerbates the progression of metabolic-associated fatty liver disease by disrupting Treg/Th17 balance. Exp Cell Res 2021; 407:112801. [PMID: 34461107 DOI: 10.1016/j.yexcr.2021.112801] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 08/21/2021] [Accepted: 08/22/2021] [Indexed: 12/12/2022]
Abstract
CD4+CD25+ regulatory T (Treg) cells and Th17 cells play important roles in the progression of metabolic-associated fatty liver disease (MAFLD). However, the contribution of monokine induced by interferon-gamma (MIG)/CXCL9 to the Treg/Th17 imbalance in MAFLD is only partially understood. In the present study, we detected increased levels of MIG/CXCL9 and a Treg/Th17 imbalance in the setting of metabolic-associated steatohepatitis (MASH). Recombinant adeno-associated virus-mediated gene transfer and silencing of MIG/CXCL9 expression in mice alleviated MASH and increased the Treg/Th17 ratio. Furthermore, the percentage of Th17 cells, but not Treg cells, differentiated from splenic CD4+ T cells was significantly increased by administration of MIG/CXCL9. MIG/CXCL9 also promoted Th17 cell proliferation, and its effects were dose dependent. Levels of phosphorylated c-Jun N-terminal kinase (JNK) decreased dramatically when MIG/CXCL9 was inhibited in a murine MASH model. In cultured Treg cells, phosphorylated JNK levels decreased dose-dependently in response to MIG/CXCL9 inhibition, but increased in cultured Th17 cells. This effect was blocked in the presence of a JNK inhibitor. These findings underline the fundamental importance of MIG/CXCL9 in maintaining the Treg/Th17 balance in MAFLD and provide the foundations for a novel approach to preventing and treating MAFLD.
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Affiliation(s)
- Lili Li
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, PR China.
| | - Yujia Xia
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, PR China.
| | - Xiaoyu Ji
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, PR China.
| | - Han Wang
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, PR China.
| | - Zerui Zhang
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, PR China.
| | - Panpan Lu
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, PR China.
| | - Qiang Ding
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, PR China.
| | - Deqiong Wang
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, PR China.
| | - Mei Liu
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, PR China.
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Wang L, Wei Y, Hu H, Zhang X, Zheng M, Fei G. [Correlation between Anxiety, Depression and Changes in Th17/Treg and Inflammatory Levels in Patients with Pulmonary Nodules]. ZHONGGUO FEI AI ZA ZHI = CHINESE JOURNAL OF LUNG CANCER 2021; 23:554-560. [PMID: 32702789 PMCID: PMC7406438 DOI: 10.3779/j.issn.1009-3419.2020.102.30] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
BACKGROUND The incidence of lung cancer is increasing annually. Clinicians pay special attention to lung tests during physical examinations. Due to the popularity of low-dose computed tomography, not only can lung cancer be diagnosed early, but physical examinations often reveal the presence of pulmonary nodules, an important health issue that cannot be ignored. Patients with pulmonary nodules are prone to adverse emotions such as anxiety and depression. Many studies have shown that patients with emotional disorders have immune system dysfunction and changes in inflammation levels. This study aimed to investigate the changes in anxiety, depression, the ratios of T helper cells 17 (Th17) and regulatory T cells (Tregs), and inflammation levels in patients with pulmonary nodules. METHODS A total of 143 subjects from The First Affiliated Hospital of Anhui Medical University were included from April 2019 to July 2019. All of the subjects were assessed with the Beck Anxiety Inventory (BAI) and the Beck Depression Inventory-II (BDI-II). Overall, 40 cases were healthy controls (HC) and 103 cases were patients with pulmonary nodules. The patients were divided into two groups according to the scale scores: 62 cases in a non-anxiety and non-depression (NAD) group and 41 cases in an anxiety and/or depression (AD) group. The percentage of Th17 and Tregs in the peripheral blood and inflammatory factors in the serum were detected. The absolute Th17 cell counts were calculated and the differences between the groups and correlations between these indicators were analyzed. RESULTS There were statistically significant differences in the percentage of Th17 cells, the absolute counts of Th17 and Th17/Treg cells, and the levels of interleukin-2 (IL-2), IL-6, and tumor necrosis factor-α (TNF-α) among three groups (all P<0.001). The AD group was higher than the HC and NAD groups (all P<0.05). There was no statistically significant difference between the HC and NAD groups (all P>0.05). The previously described indicators had no significant correlation with the severity of anxiety and depression (P>0.05). There were no significant differences in the percentage of Tregs or levels of IL-4 and IL-10 between the groups (all P>0.05). The proportion of anxiety and/or depression in female patients with pulmonary nodules was higher than that in males (P<0.05). CONCLUSIONS Patients with pulmonary nodules are prone to varying degrees of anxiety and depression, which leads to immune dysfunction and low-grade inflammation.
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Affiliation(s)
- Lina Wang
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China.,Department of Interventional Pulmonary Disease, Anhui Chest Hospital, Hefei 230022, China
| | - Yuanyuan Wei
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China
| | - Huaqing Hu
- Department of Health Examination Center, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China
| | - Xiaoyu Zhang
- Department of Health Examination Center, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China
| | - Meijuan Zheng
- Department of Clinical Laboratory, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China
| | - Guanghe Fei
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China
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18
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Zhu X, Liu L, Wang Y, Cong J, Lin Z, Wang Y, Liu Q, Wang L, Yang B, Li T. lncRNA MIAT/HMGB1 Axis Is Involved in Cisplatin Resistance via Regulating IL6-Mediated Activation of the JAK2/STAT3 Pathway in Nasopharyngeal Carcinoma. Front Oncol 2021; 11:651693. [PMID: 34094941 PMCID: PMC8173225 DOI: 10.3389/fonc.2021.651693] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Accepted: 04/06/2021] [Indexed: 12/11/2022] Open
Abstract
Cisplatin-based chemotherapy and radiotherapy are the main first-line treatment strategies for nasopharyngeal carcinoma (NPC) patients. Unfortunately, resistance is a major obstacle in the clinical management of NPC patients. We prove that the expression level of high-mobility group box 1 (HMGB1) is dramatically increased in resistant NPC cells than that in sensitive cells. HMGB1 induces the expression and secretion of IL6, which leads to constitutive autocrine activation of the JAK2/STAT3 pathway and eventually contributes to chemoresistance in NPC cells. Long non-coding RNAs (lncRNAs) have been identified as key regulators involved in drug resistance. In this study, using GO analysis of the biological process and differential expression analysis, we find 12 significantly altered IncRNAs in NPC cell lines, which may be involved in regulating gene expression. Furthermore, we determine that elevated lncRNA MIAT level upregulates HMGB1 expression, contributing to cisplatin resistance in NPC cells. We find that the deficiency of the lncRNA MIAT/HMGB1 axis, inhibition of JAK2/STAT3, or neutralization of IL6 by antibodies significantly re-sensitizes resistant NPC cells to cisplatin in resistant NPC cells. Moreover, we provide the in vivo evidence that the deficiency of HMGB1 reduces cisplatin-resistant tumor growth. Most importantly, we provide clinical evidence showing that the expression level of the lncRNA MIAT/HMGB1/IL6 axis is elevated in resistant NPC tumors, which is highly correlated with poor clinical outcome. Our findings identify a novel chemoresistance mechanism regulated by the lncRNA MIAT/HMGB1/IL6 axis, which indicates the possibilities for lncRNA MIAT, HMGB1, and IL6 as biomarkers for chemoresistance and targets for developing novel strategies to overcome resistance in NPC patients.
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Affiliation(s)
- Xuewei Zhu
- Department of Otolaryngology Head & Neck Surgery, China Japan Union Hospital of Jilin University, Changchun, China
| | - Li Liu
- Reproductive Medical Center, Department of Gynecology and Obstetrics, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Yang Wang
- Department of Dermatology, The Affiliated Hospital of Changchun University of Chinese Medicine, Changchun, China
| | - Jianan Cong
- Department of Ophthalmology, Changchun City Central Hospital, Changchun, China
| | - Zhang Lin
- Department of Ophthalmology, China-Japan Union Hospital, Jilin University, Changchun, China
| | - Yongsen Wang
- Technology Department, Harbin Boshixuan Technology Co., Ltd, Harbin, China
| | - Qi Liu
- Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States
| | - Leiming Wang
- Shenzhen Bay Laboratory, The Institute of Chemical Biology, Gaoke International Innovation Center, Shenzhen, China
| | - Ben Yang
- Department of Ophthalmology, China-Japan Union Hospital, Jilin University, Changchun, China
| | - Tao Li
- Department of Anesthesiology, China-Japan Union Hospital of Jilin University, Changchun, China
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19
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Zhou M, Zhang Y, Tang R, Liu H, Du M, Gao Z, Ji Z, Fang H. HMGB1/TLR4 Signaling Affects Regulatory T Cells in Acute Lung Injury. J Inflamm Res 2021; 14:1551-1561. [PMID: 33907436 PMCID: PMC8064684 DOI: 10.2147/jir.s302967] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Accepted: 03/31/2021] [Indexed: 12/18/2022] Open
Abstract
Background High-mobility group box-1 protein (HMGB1) serves as the prototypic damage-associated molecular pattern molecule, and TLR4 is considered a receptor for HMGB1. Regulatory T cells (Tregs) play a crucial role in infectious diseases. The role of HMGB1 in the modulation of Tregs is of great interest. Methods Serum HMGB1 and Treg proportions were detected in 58 patients with acute lung injury (ALI) and 36 healthy volunteers. The correlations of these parameters with disease severity were analyzed. The WT and TLR4-/- mice were administered HMGB1 by intratracheal injection. After 48 h, the mice were sacrificed. The morphological changes and wet/dry ratio of the lung were measured. Spleen CD4+CD25+ Tregs were sorted from spleen cells, the expression of FOXP3 and CTLA-4, and releasing of cytokines was detected. CD4+CD25+ Tregs were cocultured with effector T cells, the inhibitory effect, and release of cytokines was detected. Results Significantly increased plasma levels of HMGB1 and reduced CD4+CD25+CD127low Tregs were detected in ALI patients. In the mouse model, lung injury was significantly increased after HMGB1 instillation in the WT and TLR4-/- groups compared with control group. The lung wet/dry ratio and the TNF-α and IL-1β contents in BALF were significantly increased, and the severity of WT mice was higher than that of TLR4-/- mice. The expression of FOXP3 and CTLA-4 in TLR4-/- mice was significantly increased compared with that in WT mice and was associated with a similar trend of IL-10 and TGF-β levels (p<0.05). In coculture with effector T cells, Tregs isolated from TLR4-/- mice exhibited decreased IL-2 and IFN-γ and increased IL-4 levels compared with Tregs from WT mice. Increased polarization of TLR4-/- CD4+CD25+ Treg cells to Th2 cells was observed. Conclusion In HMGB1-induced lung injury, HMGB1 affects the expression of FOXP3 and CTLA-4 through TLR4, thus reducing the immunosuppressive function of Treg cells.
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Affiliation(s)
- Min Zhou
- Neurocritical Care Unit, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, People's Republic of China
| | - Yadi Zhang
- Department of Respiratory Medicine, The Second People's Hospital of Hefei and Hefei Hospital Affiliated with Anhui Medical University, Hefei, Anhui, 230011, People's Republic of China
| | - Rui Tang
- Neurocritical Care Unit, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, People's Republic of China
| | - Haiyan Liu
- Neurocritical Care Unit, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, People's Republic of China
| | - Min Du
- Neurocritical Care Unit, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, People's Republic of China
| | - Zhi Gao
- Neurocritical Care Unit, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, People's Republic of China
| | - Zongshu Ji
- Neurocritical Care Unit, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, People's Republic of China
| | - Haoshu Fang
- Department of Pathophysiology, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui, 230032, People's Republic of China
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20
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Ni YA, Chen H, Nie H, Zheng B, Gong Q. HMGB1: An overview of its roles in the pathogenesis of liver disease. J Leukoc Biol 2021; 110:987-998. [PMID: 33784425 DOI: 10.1002/jlb.3mr0121-277r] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Revised: 01/06/2021] [Accepted: 02/04/2021] [Indexed: 12/15/2022] Open
Abstract
High-mobility group box 1 (HMGB1) is an abundant architectural chromosomal protein that has multiple biologic functions: gene transcription, DNA replication, DNA-damage repair, and cell signaling for inflammation. HMGB1 can be released passively by necrotic cells or secreted actively by activated immune cells into the extracellular milieu after injury. Extracellular HMGB1 acts as a damage-associated molecular pattern to initiate the innate inflammatory response to infection and injury by communicating with neighboring cells through binding to specific cell-surface receptors, including Toll-like receptors (TLRs) and the receptor for advanced glycation end products (RAGE). Numerous studies have suggested HMGB1 to act as a key protein mediating the pathogenesis of chronic and acute liver diseases, including nonalcoholic fatty liver disease, hepatocellular carcinoma, and hepatic ischemia/reperfusion injury. Here, we provide a detailed review that focuses on the role of HMGB1 and HMGB1-mediated inflammatory signaling pathways in the pathogenesis of liver diseases.
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Affiliation(s)
- Yuan-Ao Ni
- Department of Immunology, School of Medicine, Yangtze University, Jingzhou, Hubei Province, People's Republic of China
| | - Hui Chen
- Department of Immunology, School of Medicine, Yangtze University, Jingzhou, Hubei Province, People's Republic of China
| | - Hao Nie
- Department of Immunology, School of Medicine, Yangtze University, Jingzhou, Hubei Province, People's Republic of China.,Clinical Molecular Immunology Center, School of Medicine, Yangtze University, Jingzhou, Hubei Province, People's Republic of China
| | - Bing Zheng
- Department of Immunology, School of Medicine, Yangtze University, Jingzhou, Hubei Province, People's Republic of China.,Clinical Molecular Immunology Center, School of Medicine, Yangtze University, Jingzhou, Hubei Province, People's Republic of China
| | - Quan Gong
- Department of Immunology, School of Medicine, Yangtze University, Jingzhou, Hubei Province, People's Republic of China.,Clinical Molecular Immunology Center, School of Medicine, Yangtze University, Jingzhou, Hubei Province, People's Republic of China
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21
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Astragali Radix Contributes to the Inhibition of Liver Fibrosis via High-Mobility Group Box 1-Mediated Inflammatory Signaling Pathway. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2021; 2021:5574010. [PMID: 33790974 PMCID: PMC7984916 DOI: 10.1155/2021/5574010] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/09/2021] [Revised: 02/26/2021] [Accepted: 03/02/2021] [Indexed: 12/20/2022]
Abstract
Astragali Radix (AR), the dried root of Astragali Radix membranaceus (Fisch.) Bge. or Astragali Radix membranaceus (Fisch.) Bge. var. mongholicus (Bge) Hsiao, is a commonly used traditional Chinese medicine for the treatment of liver diseases. This study aimed to comprehensively evaluate the pharmacological action and explore the potential mechanism of AR on liver fibrosis. Rats were administered with carbon tetrachloride for eight weeks, followed by oral treatment with AR for six weeks. The efficacy was confirmed by measuring liver function and liver fibrosis levels. The underlying mechanisms were explored by detecting the expression of related proteins. AR significantly decreased the serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), collagen IV (COL-IV), hyaluronic acid (HA), laminin (LN), and precollagen type III (PCIII). In addition, AR inhibited the deposition of collagen and the activation of hepatic stellate cells. Those data strongly demonstrated that AR alleviated liver fibrosis by CCl4. In order to illustrate the potential inflammatory, the mRNA levels of IL-6, TNF-α, and IL-1β were detected. Subsequently, immunohistochemistry analysis was performed to further verify the expression of type I collagen. Finally, the expression of key proteins in the inflammatory signaling pathway was detected. AR significantly reduced the expression of high-mobility group box 1 (HMGB1), TLR4, Myd88, RAGE, and NF-κ B p65 genes and proteins. In addition, western blotting showed AR decreased the protein expression of RAGE, p-MEK1/2, p-ERK1/2, and p-c-Jun. Taken together, our data reveal that AR significantly inhibits liver fibrosis by intervening in the HMGB1-mediated inflammatory signaling pathway and secretion signaling pathway. This study will provide valuable references for the in-depth research and development of Astragali Radix against liver fibrosis.
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22
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Abdulla OA, Neamah W, Sultan M, Chatterjee S, Singh N, Nagarkatti M, Nagarkatti P. AhR Ligands Differentially Regulate miRNA-132 Which Targets HMGB1 and to Control the Differentiation of Tregs and Th-17 Cells During Delayed-Type Hypersensitivity Response. Front Immunol 2021; 12:635903. [PMID: 33679792 PMCID: PMC7933657 DOI: 10.3389/fimmu.2021.635903] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Accepted: 01/28/2021] [Indexed: 12/20/2022] Open
Abstract
Aryl hydrocarbon receptor (AhR), is a transcription factor and an environmental sensor that has been shown to regulate T cell differentiation. Interestingly, AhR ligands exert varying effects from suppression to exacerbation of inflammation through induction of Tregs and Th-17 cells, respectively. In the current study, we investigated whether the differential effects of AhR ligands on T cell differentiation are mediated by miRNA during delayed-type hypersensitivity (DTH) reaction against methylated Bovine Serum Albumin (mBSA). Treatment of C57BL/6 mice with TCDD attenuated mBSA-mediated DTH response, induced Tregs, decreased Th-17 cells, and caused upregulation of miRNA-132. TCDD caused an increase in several Treg subsets including inducible peripheral, natural thymic, and Th3 cells. Also, TCDD increased TGF-β and Foxp3 expression. In contrast, treating mice with FICZ exacerbated the DTH response, induced inflammatory Th17 cells, induced IL-17, and RORγ. Analysis of miRNA profiles from draining lymph nodes showed that miR-132 was upregulated in the TCDD group and downregulated in the FICZ group. Transfection studies revealed that miRNA-132 targeted High Mobility Group Box 1 (HMGB1). Downregulation of HMGB1 caused an increase in FoxP3+ Treg differentiation and suppression of Th-17 cells while upregulation of HMGB1 caused opposite effects. Moreover, TCDD was less effective in suppressing DTH response and induction of Tregs in mice that were deficient in miR-132. In summary, this study demonstrates that TCDD and FICZ have divergent effects on DTH response and T cell differentiation, which is mediated through, at least in part, regulation of miRNA-132 that targets HMGB1.
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MESH Headings
- Animals
- Basic Helix-Loop-Helix Transcription Factors/agonists
- Basic Helix-Loop-Helix Transcription Factors/metabolism
- Carbazoles/toxicity
- Cell Differentiation/drug effects
- Cells, Cultured
- Cytokines/genetics
- Cytokines/metabolism
- Disease Models, Animal
- Female
- Forkhead Transcription Factors/genetics
- Forkhead Transcription Factors/metabolism
- HMGB1 Protein/genetics
- HMGB1 Protein/metabolism
- Hypersensitivity, Delayed/genetics
- Hypersensitivity, Delayed/immunology
- Hypersensitivity, Delayed/metabolism
- Hypersensitivity, Delayed/prevention & control
- Ligands
- Mice, Inbred C57BL
- Mice, Knockout
- MicroRNAs/genetics
- MicroRNAs/metabolism
- Phenotype
- Polychlorinated Dibenzodioxins/toxicity
- Receptors, Aryl Hydrocarbon/agonists
- Receptors, Aryl Hydrocarbon/metabolism
- T-Lymphocytes, Regulatory/drug effects
- T-Lymphocytes, Regulatory/immunology
- T-Lymphocytes, Regulatory/metabolism
- Th17 Cells/drug effects
- Th17 Cells/immunology
- Th17 Cells/metabolism
- Mice
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Affiliation(s)
- Osama A. Abdulla
- Department of Pathology, Microbiology and Immunology, School of Medicine, University of South Carolina, Columbia, SC, United States
| | - Wurood Neamah
- Department of Pathology, Microbiology and Immunology, School of Medicine, University of South Carolina, Columbia, SC, United States
| | - Muthanna Sultan
- Department of Pathology, Microbiology and Immunology, School of Medicine, University of South Carolina, Columbia, SC, United States
| | - Saurabh Chatterjee
- Environmental Health and Disease Laboratory, Department of Environmental Health Sciences, Arnold School of Public Health, University of South Carolina, Columbia, SC, United States
| | - Narendra Singh
- Department of Pathology, Microbiology and Immunology, School of Medicine, University of South Carolina, Columbia, SC, United States
| | - Mitzi Nagarkatti
- Department of Pathology, Microbiology and Immunology, School of Medicine, University of South Carolina, Columbia, SC, United States
| | - Prakash Nagarkatti
- Department of Pathology, Microbiology and Immunology, School of Medicine, University of South Carolina, Columbia, SC, United States
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23
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Xie K, Chen YQ, Chai YS, Lin SH, Wang CJ, Xu F. HMGB1 suppress the expression of IL-35 by regulating Naïve CD4+ T cell differentiation and aggravating Caspase-11-dependent pyroptosis in acute lung injury. Int Immunopharmacol 2021; 91:107295. [PMID: 33360086 DOI: 10.1016/j.intimp.2020.107295] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Revised: 12/08/2020] [Accepted: 12/09/2020] [Indexed: 02/07/2023]
Abstract
OBJECTIVES Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) is a severe form of inflammatory lung disease. Its development and progression are regulated by cytokines. The purpose of this study was to determine the effects of HMGB1 involved in the regulation of Treg cells and IL-35. METHODS A cecal ligation and puncture (CLP)-induced ALI model was used to investigate the changes in IL-35, Tregs, and the expression of RAGE and caspase-11 after HMGB1 inhibition (glycyrrhizin was used as an inhibitor of HMGB1). CD4+ naïve T cells sorted from C57BL/6 mice spleens were cultured to explore the role of HMGB1 in the differentiation from CD4+ naïve T cells to Tregs. RESULTS HMGB1 promoted lung injury and uncontrolled inflammation in the CLP mouse model. HMGB1, NF-κB p65, RAGE, and caspase-11 expression in the lungs of CLP mice decreased significantly after pretreatment with glycyrrhizin. We found that the Treg proportion and IL-35 expression were upregulated in the serum and lung of CLP mice after inhibiting HMGB1. In our in vitro experiments, we found that recombinant HMGB1 significantly suppressed the proportion of CD4+CD25+FOXP3+Tregs differentiated from CD4+ naïve T cells. CONCLUSIONS The inhibition of HMGB1 increased the proportion of Treg and expression of IL-35 and alleviated lung injury in the CLP-induced ALI model. Furthermore, inhibition of HMGB1 reduced caspase-11-dependent pyroptosis in the lungs of the CLP-induced ALI model.
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Affiliation(s)
- Ke Xie
- Department of Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yan-Qing Chen
- Department of Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yu-Sen Chai
- Department of Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Shi-Hui Lin
- Department of Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Chuan-Jiang Wang
- Department of Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
| | - Fang Xu
- Department of Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
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24
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Tamtaji OR, Milajerdi A, Reiner Ž, Dadgostar E, Amirani E, Asemi Z, Mirsafaei L, Mansournia MA, Dana PM, Sadoughi F, Hallajzadeh J. Effects of flaxseed oil supplementation on biomarkers of inflammation and oxidative stress in patients with metabolic syndrome and related disorders: A systematic review and meta-analysis of randomized controlled trials. Clin Nutr ESPEN 2020; 40:27-33. [DOI: 10.1016/j.clnesp.2020.09.017] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Revised: 06/27/2020] [Accepted: 09/14/2020] [Indexed: 12/15/2022]
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25
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Liang X, Zhang X, Lian K, Tian X, Zhang M, Wang S, Chen C, Nie C, Pan Y, Han F, Wei Z, Zhang W. Antiviral effects of Bovine antimicrobial peptide against TGEV in vivo and in vitro. J Vet Sci 2020; 21:e80. [PMID: 33016025 PMCID: PMC7533394 DOI: 10.4142/jvs.2020.21.e80] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Revised: 07/23/2020] [Accepted: 08/11/2020] [Indexed: 12/14/2022] Open
Abstract
Background In suckling piglets, transmissible gastroenteritis virus (TGEV) causes lethal diarrhea accompanied by high infection and mortality rates, leading to considerable economic losses. This study explored methods of preventing or inhibiting their production. Bovine antimicrobial peptide-13 (APB-13) has antibacterial, antiviral, and immune functions. Objectives This study analyzed the efficacy of APB-13 against TGEV through in vivo and in vitro experiments. Methods The effects of APB-13 toxicity and virus inhibition rate on swine testicular (ST) cells were detected using 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide (MTT). The impact of APB-13 on virus replication was examined through the 50% tissue culture infective dose (TCID50). The mRNA and protein levels were investigated by real-time quantitative polymerase chain reaction and western blot (WB). Tissue sections were used to detect intestinal morphological development. Results The safe and effective concentration range of APB-13 on ST cells ranged from 0 to 62.5 µg/mL, and the highest viral inhibitory rate of APB-13 was 74.1%. The log10TCID50 of 62.5 µg/mL APB-13 was 3.63 lower than that of the virus control. The mRNA and protein expression at 62.5 µg/mL APB-13 was significantly lower than that of the virus control at 24 hpi. Piglets in the APB-13 group showed significantly lower viral shedding than that in the virus control group, and the pathological tissue sections of the jejunum morphology revealed significant differences between the groups. Conclusions APB-13 exhibited good antiviral effects on TGEV in vivo and in vitro.
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Affiliation(s)
- Xiuli Liang
- College of Animal Science and Technology, Shihezi University, Shihezi, Xinjiang 832000, China.,Henan Joint International Research Laboratory of Veterinary Biologics Research and Application, Henan Provincial Animal Disease Prevention and Control and Nutrition Immunization Academician workstation, Anyang Institute of Technology, Anyang, Henan 455000, China
| | - Xiaojun Zhang
- Henan Joint International Research Laboratory of Veterinary Biologics Research and Application, Henan Provincial Animal Disease Prevention and Control and Nutrition Immunization Academician workstation, Anyang Institute of Technology, Anyang, Henan 455000, China
| | - Kaiqi Lian
- Henan Joint International Research Laboratory of Veterinary Biologics Research and Application, Henan Provincial Animal Disease Prevention and Control and Nutrition Immunization Academician workstation, Anyang Institute of Technology, Anyang, Henan 455000, China
| | - Xiuhua Tian
- Anyang County Agricultural and Rural Bureau, Anyang, Henan 455000, China
| | - Mingliang Zhang
- Henan Joint International Research Laboratory of Veterinary Biologics Research and Application, Henan Provincial Animal Disease Prevention and Control and Nutrition Immunization Academician workstation, Anyang Institute of Technology, Anyang, Henan 455000, China
| | - Shiqiong Wang
- College of Animal Husbandry, Henan Agricultural University, Zhengzhou, Henan 450000, China
| | - Cheng Chen
- College of Animal Science and Technology, Shihezi University, Shihezi, Xinjiang 832000, China
| | - Cunxi Nie
- College of Animal Science and Technology, Shihezi University, Shihezi, Xinjiang 832000, China
| | - Yun Pan
- Henan Yihongshancheng Bio-Tech Co. Ltd, Wuzhi, Henan 454950, China
| | - Fangfang Han
- College of Animal Husbandry, Henan Agricultural University, Zhengzhou, Henan 450000, China
| | - Zhanyong Wei
- College of Animal Husbandry, Henan Agricultural University, Zhengzhou, Henan 450000, China.
| | - Wenju Zhang
- College of Animal Science and Technology, Shihezi University, Shihezi, Xinjiang 832000, China.
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26
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A systematic review and meta-analysis: The effects of probiotic supplementation on metabolic profile in patients with neurological disorders. Complement Ther Med 2020; 53:102507. [PMID: 33066850 DOI: 10.1016/j.ctim.2020.102507] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Revised: 07/08/2020] [Accepted: 07/08/2020] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND AND OBJECTIVE The objective of meta-analysis of randomized controlled trials (RCTs) was to evaluate the effects of probiotic supplementation on metabolic status in patients with neurological disorders. METHODS The following databases were search up to April 2019: Pubmed, Scopus, Google scholar, Web of Science, and Cochrane Central Register of Controlled Trials. The quality of the relevant extracted data was assessed according to the Cochrane risk of bias tool. Data were pooled by the use of the inverse variance method and expressed as mean difference with 95 % Confidence Intervals (95 % CI). RESULTS Nine studies were included in this meta-analysis. The findings suggested that probiotic supplementation resulted in a significant reduction in C-reactive protein (CRP) [Weighted Mean Difference (WMD): -1.06; 95 % CI: -1.80, -0.32] and malondialdehyde (MDA) levels (WMD: -0.32; 95 % CI: -0.46, -0.18). Supplementation with probiotics also significantly reduced insulin (WMD: -3.02; 95 % CI: -3.88, -2.15) and homeostatic model assessment for insulin resistance (HOMA-IR) (WMD: -0.71; 95 % CI: -0.89, -0.52). Probiotics significantly reduced triglycerides (WMD: -18.38; 95 % CI: -25.50, -11.26) and VLDL-cholesterol (WMD: -3.16; 95 % CI: -4.53, -1.79), while they increased HDL-cholesterol levels (WMD: 1.52; 95 % CI: 0.29, 2.75). CONCLUSION This meta-analysis demonstrated that taking probiotic by patients with neurological disorders had beneficial effects on CRP, MDA, insulin, HOMA-IR, triglycerides, VLDL-cholesterol and HDL-cholesterol levels, but did not affect other metabolic parameters.
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Zhang J, Chen L, Wang F, Zou Y, Li J, Luo J, Khan F, Sun F, Li Y, Liu J, Chen Z, Zhang S, Xiong F, Yu Q, Li J, Huang K, Adam BL, Zhou Z, Eizirik DL, Yang P, Wang CY. Extracellular HMGB1 exacerbates autoimmune progression and recurrence of type 1 diabetes by impairing regulatory T cell stability. Diabetologia 2020; 63:987-1001. [PMID: 32072192 PMCID: PMC7145789 DOI: 10.1007/s00125-020-05105-8] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2019] [Accepted: 01/15/2020] [Indexed: 01/07/2023]
Abstract
AIMS/HYPOTHESIS High-mobility group box 1 (HMGB1), an evolutionarily conserved chromosomal protein, was rediscovered to be a 'danger signal' (alarmin) that alerts the immune system once released extracellularly. Therefore, it has been recognised contributing to the pathogenesis of autoimmune diabetes, but its exact impact on the initiation and progression of type 1 diabetes, as well as the related molecular mechanisms, are yet to be fully characterised. METHODS In the current report, we employed NOD mice as a model to dissect the impact of blocking HMGB1 on the prevention, treatment and reversal of type 1 diabetes. To study the mechanism involved, we extensively examined the characteristics of regulatory T cells (Tregs) and their related signalling pathways upon HMGB1 stimulation. Furthermore, we investigated the relevance of our data to human autoimmune diabetes. RESULTS Neutralising HMGB1 both delayed diabetes onset and, of particular relevance, reversed diabetes in 13 out of 20 new-onset diabetic NOD mice. Consistently, blockade of HMGB1 prevented islet isografts from autoimmune attack in diabetic NOD mice. Using transgenic reporter mice that carry a Foxp3 lineage reporter construct, we found that administration of HMGB1 impairs Treg stability and function. Mechanistic studies revealed that HMGB1 activates receptor for AGE (RAGE) and toll-like receptor (TLR)4 to enhance phosphatidylinositol 3-kinase (PI3K)-Akt-mechanistic target of rapamycin (mTOR) signalling, thereby impairing Treg stability and functionality. Indeed, high circulating levels of HMGB1 in human participants with type 1 diabetes contribute to Treg instability, suggesting that blockade of HMGB1 could be an effective therapy against type 1 diabetes in clinical settings. CONCLUSIONS/INTERPRETATION The present data support the possibility that HMGB1 could be a viable therapeutic target to prevent the initiation, progression and recurrence of autoimmunity in the setting of type 1 diabetes.
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Affiliation(s)
- Jing Zhang
- The Center for Biomedical Research, Tongji Hospital Research Building, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, Caidian, China
- Department of Respiratory and Critical Care Medicine, NHC Key Laboratory of Respiratory Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Longmin Chen
- The Center for Biomedical Research, Tongji Hospital Research Building, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, Caidian, China
- Department of Respiratory and Critical Care Medicine, NHC Key Laboratory of Respiratory Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Faxi Wang
- The Center for Biomedical Research, Tongji Hospital Research Building, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, Caidian, China
- Department of Respiratory and Critical Care Medicine, NHC Key Laboratory of Respiratory Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yuan Zou
- The Center for Biomedical Research, Tongji Hospital Research Building, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, Caidian, China
- Department of Respiratory and Critical Care Medicine, NHC Key Laboratory of Respiratory Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jingyi Li
- The Center for Biomedical Research, Tongji Hospital Research Building, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, Caidian, China
| | - Jiahui Luo
- The Center for Biomedical Research, Tongji Hospital Research Building, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, Caidian, China
- Department of Respiratory and Critical Care Medicine, NHC Key Laboratory of Respiratory Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Faheem Khan
- The Center for Biomedical Research, Tongji Hospital Research Building, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, Caidian, China
| | - Fei Sun
- The Center for Biomedical Research, Tongji Hospital Research Building, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, Caidian, China
- Department of Respiratory and Critical Care Medicine, NHC Key Laboratory of Respiratory Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yang Li
- The Center for Biomedical Research, Tongji Hospital Research Building, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, Caidian, China
- Department of Respiratory and Critical Care Medicine, NHC Key Laboratory of Respiratory Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jing Liu
- The Center for Biomedical Research, Tongji Hospital Research Building, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, Caidian, China
- Department of Respiratory and Critical Care Medicine, NHC Key Laboratory of Respiratory Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhishui Chen
- The Center for Biomedical Research, Tongji Hospital Research Building, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, Caidian, China
- Key Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Tongji Hospital, Wuhan, China
| | - Shu Zhang
- The Center for Biomedical Research, Tongji Hospital Research Building, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, Caidian, China
- Department of Respiratory and Critical Care Medicine, NHC Key Laboratory of Respiratory Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Fei Xiong
- The Center for Biomedical Research, Tongji Hospital Research Building, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, Caidian, China
- Department of Respiratory and Critical Care Medicine, NHC Key Laboratory of Respiratory Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qilin Yu
- The Center for Biomedical Research, Tongji Hospital Research Building, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, Caidian, China
| | - Jinxiu Li
- Shenzhen Third People's Hospital, Shenzhen, Guangdong, China
| | - Kun Huang
- Tongji School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Bao-Ling Adam
- Department of Surgery, Medical College of Georgia at Augusta University, Augusta, GA, USA
| | - Zhiguang Zhou
- Diabetes Center, The Second Xiangya Hospital, Institute of Metabolism and Endocrinology, Central South University, Changsha, China
| | - Decio L Eizirik
- ULB Center for Diabetes Research, Université Libre de Bruxelles, Brussels, Belgium
| | - Ping Yang
- The Center for Biomedical Research, Tongji Hospital Research Building, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, Caidian, China.
- Department of Respiratory and Critical Care Medicine, NHC Key Laboratory of Respiratory Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Cong-Yi Wang
- The Center for Biomedical Research, Tongji Hospital Research Building, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, Caidian, China.
- Department of Respiratory and Critical Care Medicine, NHC Key Laboratory of Respiratory Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
- Key Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Tongji Hospital, Wuhan, China.
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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: 714] [Impact Index Per Article: 142.8] [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.
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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
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Alvarez F, Al-Aubodah TA, Yang YH, Piccirillo CA. Mechanisms of T REG cell adaptation to inflammation. J Leukoc Biol 2020; 108:559-571. [PMID: 32202345 DOI: 10.1002/jlb.1mr0120-196r] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2019] [Revised: 01/19/2020] [Accepted: 02/03/2020] [Indexed: 12/17/2022] Open
Abstract
Inflammation is an important defense mechanism. In this complex and dynamic process, drastic changes in the tissue micro-environment play key roles in dictating the nature of the evolving immune response. However, uncontrolled inflammation is detrimental, leading to unwanted cellular damage, loss of physiological functions, and even death. As such, the immune system possesses tools to limit inflammation while ensuring rapid and effective clearance of the inflammatory trigger. Foxp3+ regulatory T (TREG ) cells, a potently immunosuppressive CD4+ T cell subset, play a crucial role in immune tolerance by controlling the extent of the response to self and non-self Ags, all-the-while promoting a quick return to immune homeostasis. TREG cells adapt to changes in the local micro-environment enabling them to migrate, proliferate, survive, differentiate, and tailor their suppressive ability at inflamed sites. Several inflammation-associated factors can impact TREG cell functional adaptation in situ including locally released alarmins, oxygen availability, tissue acidity and osmolarity and nutrient availability. Here, we review some of these key signals and pathways that control the adaptation of TREG cell function in inflammatory settings.
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Affiliation(s)
- Fernando Alvarez
- Department of Microbiology and Immunology, McGill University, Montréal, Québec, Canada.,Program in Infectious Diseases and Immunology in Global Health, Centre for Translational Biology, Research Institute of the McGill University Health Centre, Montréal, Québec, Canada.,Centre of Excellence in Translational Immunology (CETI), Montréal, Québec, Canada
| | - Tho-Alfakar Al-Aubodah
- Department of Microbiology and Immunology, McGill University, Montréal, Québec, Canada.,Program in Infectious Diseases and Immunology in Global Health, Centre for Translational Biology, Research Institute of the McGill University Health Centre, Montréal, Québec, Canada.,Centre of Excellence in Translational Immunology (CETI), Montréal, Québec, Canada
| | - Yujian H Yang
- Program in Infectious Diseases and Immunology in Global Health, Centre for Translational Biology, Research Institute of the McGill University Health Centre, Montréal, Québec, Canada.,Centre of Excellence in Translational Immunology (CETI), Montréal, Québec, Canada.,Division of Experimental Medicine, Department of Medicine, McGill University, Montréal, Québec, Canada
| | - Ciriaco A Piccirillo
- Department of Microbiology and Immunology, McGill University, Montréal, Québec, Canada.,Program in Infectious Diseases and Immunology in Global Health, Centre for Translational Biology, Research Institute of the McGill University Health Centre, Montréal, Québec, Canada.,Centre of Excellence in Translational Immunology (CETI), Montréal, Québec, Canada.,Division of Experimental Medicine, Department of Medicine, McGill University, Montréal, Québec, Canada
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Nobiletin suppresses IL-21/IL-21 receptor-mediated inflammatory response in MH7A fibroblast-like synoviocytes (FLS): An implication in rheumatoid arthritis. Eur J Pharmacol 2020; 875:172939. [PMID: 31978425 DOI: 10.1016/j.ejphar.2020.172939] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2019] [Revised: 12/17/2019] [Accepted: 01/17/2020] [Indexed: 12/12/2022]
Abstract
The mechanisms driving the development and progression of Rheumatoid arthritis (RA) are complex, novel targeted therapies are gaining traction as potential methods to prevent or slow the progression of RA. Nobiletin is a derivative of citrus fruit that has been shown to attenuate the development of osteoarthritis and inhibit the expression of proinflammatory cytokines. However, the exact mechanisms by which nobiletin exerts these chondroprotective effects remain poorly understood. In the present study, we investigated the impact of nobiletin in mediating the effects of interleukin-21 (IL-21) in MH7A fibroblast-like synoviocytes (FLS), the main cell type found in the articular synovium. Firstly, we demonstrate that nobiletin (25 μM and 50 μM) reduced the expression of the IL-21 receptor by 29% and 51%, respectively, in FLS. Additionally, our findings demonstrate that nobiletin potently ameliorated IL-21-induced increased production of reactive oxygen species and 4-hydroxynonenal, increased expression of interleukin 6 (IL-6), tumor necrosis factor-α (TNF-α), and high-mobility group box 1 (HMGB1), and decreased mitochondrial membrane potential. We also demonstrate the ability of nobiletin to attenuate IL-21-induced expression of matrix metalloproteinases 3 and 13 (MMP-3, MMP-13), key degradative enzymes involved in RA-associated cartilage destruction. Finally, we show that the effects of nobiletin are mediated through the JAK1/STAT3 pathway, as nobiletin significantly reduced the phosphorylation of both JAK1 and STAT3. Taken together, our findings indicate that nobiletin may offer a safe and effective treatment against the development and progression of RA induced by the expression of IL-21 and its receptor.
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Wang H, Feng X, Han P, Lei Y, Xia Y, Tian D, Yan W. The JAK inhibitor tofacitinib ameliorates immune‑mediated liver injury in mice. Mol Med Rep 2019; 20:4883-4892. [PMID: 31638166 PMCID: PMC6854585 DOI: 10.3892/mmr.2019.10750] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2019] [Accepted: 08/08/2019] [Indexed: 12/18/2022] Open
Abstract
The prevalence of immune-mediated liver diseases such as autoimmune liver disease or viral hepatitis has increased in recent years, and the side effects of pre-existing treatments are a worldwide problem. Regulatory T cells (Tregs) and T helper 17 (Th17) cells play important roles in the development of immune-mediated hepatitis and may serve as potential therapeutic targets. Tofacitinib, a new Janus kinase (JAK) inhibitor, is under investigation for the treatment of rheumatoid arthritis; it is also helpful in treating ulcerative colitis and psoriasis. The roles of tofacitinib were investigated in conferring protection against immune-mediated liver injury in mice. T cell-mediated hepatitis was induced by concanavalin A (ConA). The mice in the treatment groups were administered with tofacitinib intragastrically before the ConA injection. Histopathological examination was performed by hematoxylin and eosin (H&E) staining, and the serum transaminase and inflammatory cytokine levels were determined using an automatic biochemistry analysis apparatus or cytometric bead array (CBA) kits. Flow cytometric analysis was used to detect Tregs and Th17 cells. Tofacitinib significantly decreased the hepatic injury induced by ConA and prominently decreased the liver transaminase level. The secretion of several anti-inflammatory cytokines such as interleukin (IL)-10 was upregulated in mice from the treatment group, compared to that in mice treated with ConA alone, while the expression of interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) decreased. Tofacitinib treatment increased the number of Tregs and reduced the number of Th17 cells. Furthermore, tofacitinib could relieve liver fibrosis under conditions of autoimmune hepatitis (AIH). The present results indicated that tofacitinib improved immune-mediated hepatitis and restored the impaired Treg/Th17 cell ratio, which suggests that it may serve as a novel treatment approach for immune-mediated liver diseases.
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Affiliation(s)
- Han Wang
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Xinxia Feng
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Ping Han
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Yu Lei
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Yujia Xia
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Dean Tian
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Wei Yan
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
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Strohbuecker L, Koenen H, van Rijssen E, van Cranenbroek B, Fasse E, Joosten I, Körber A, Bergmann C. Increased dermal expression of chromatin-associated protein HMGB1 and concomitant T-cell expression of the DNA RAGE in patients with psoriasis vulgaris. PSORIASIS (AUCKLAND, N.Z.) 2019; 9:7-17. [PMID: 30859087 PMCID: PMC6385765 DOI: 10.2147/ptt.s190507] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
PURPOSE Psoriasis vulgaris (PV) is an autoimmune-related chronic inflammatory disease of the skin, with both vascular and metabolic effects. Aggravating factors have been identified that initiate and maintain inflammation, including expression of Th1-, Th17-, and Th22-cell derived cytokines. Recently, we showed that the evolutionarily ancient and highly conserved damage-associated molecular pattern molecule "high mobility group box 1 (HMGB1)" is significantly increased in the serum of PV patients with disease progression and is decreased under standard therapies. MATERIALS AND METHODS To better understand the role of HMGB1 in the pathogenesis of PV, we recruited 22 untreated psoriatic patients with either mild or severe disease, defined by the Psoriasis Area Severity Index. We assessed HMGB1 and receptor for advanced glycation end products (RAGE) expression in the skin by immunohistochemistry and analyzed the immune-phenotype of Treg and Th17 cells by flow cytometry. RESULTS We found increased staining for HMGB1 in the dermis of psoriatic plaques in comparison to uninvolved skin of patients with PV. In addition, the major histocompatibility complex class III-encoded DNA and HMGB1 RAGE, induced by HMGB1, were highly expressed on psoriatic CD8+ T cells and CD4+ Treg. High expression of HMGB1 in the lesional skin was associated with even higher expression of its receptor, RAGE, on the cell surface of keratino-cytes in patients with severe PV. CONCLUSION The presence of HMGB1 and RAGE signaling may impact orchestration of chronic inflammation in PV which might have implications for Treg and Th17 cells.
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Affiliation(s)
- Lisa Strohbuecker
- Department of Dermatology, University Hospital Essen, 45147 Essen, Germany
| | - Hans Koenen
- Department of Laboratory Medicine, Laboratory of Medical Immunology, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Esther van Rijssen
- Department of Laboratory Medicine, Laboratory of Medical Immunology, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Bram van Cranenbroek
- Department of Laboratory Medicine, Laboratory of Medical Immunology, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Esther Fasse
- Department of Laboratory Medicine, Laboratory of Medical Immunology, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Irma Joosten
- Department of Laboratory Medicine, Laboratory of Medical Immunology, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Andreas Körber
- Department of Dermatology, University Hospital Essen, 45147 Essen, Germany
| | - Christoph Bergmann
- Department of Otorhinolaryngology, University Hospital Essen, 45147 Essen, Germany,
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Osborne LM, Brar A, Klein SL. The role of Th17 cells in the pathophysiology of pregnancy and perinatal mood and anxiety disorders. Brain Behav Immun 2019; 76:7-16. [PMID: 30465878 PMCID: PMC6359933 DOI: 10.1016/j.bbi.2018.11.015] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2018] [Revised: 10/19/2018] [Accepted: 11/18/2018] [Indexed: 12/27/2022] Open
Abstract
T cells play a key role in adaptive immune responses, and shifts among T cell classes occur in normal pregnancy. There is evidence for the role of TH17 cells and dysregulation of the TH17/Treg cell balance in morbidities and autoimmune diseases during pregnancy. Because TH17 responses may play a role in depression and anxiety outside of pregnancy, we hypothesize that TH17 responses and the balance of TH17/Treg activity may also contribute to the development of depression and anxiety during pregnancy. To explore this hypothesis, this review has three main aims: 1) to evaluate systematically the role of TH17 cells and cytokines during pregnancy; 2) to compare changes in the ratio of TH17/Treg cells during pregnancy morbidities with the changes that occur in depression and anxiety outside of pregnancy; and 3) to provide a basis for further research on TH17 cells in perinatal mood and anxiety disorders, with an eye toward the development of novel therapeutics. We also review the limited literature concerning perinatal mood and anxiety disorders, and hypothesize about the potential role of TH17 cells in these illnesses. Understanding the pathophysiology of perinatal mood and anxiety disorders will aid development of novel therapeutics that address immunological mechanisms, in addition to the serotonin system, which are targetable molecules in treating depression and anxiety during pregnancy.
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Affiliation(s)
- Lauren M. Osborne
- Women’s Mood Disorders Center, Departments of Psychiatry & Behavioral Sciences, and of Gynecology & Obstetrics, Johns Hopkins University School of Medicine, Baltimore, MD 21205
| | - Amitoj Brar
- Women’s Mood Disorders Center, Departments of Psychiatry & Behavioral Sciences, and of Gynecology & Obstetrics, Johns Hopkins University School of Medicine, Baltimore, MD 21205
| | - Sabra L. Klein
- W. Harry Feinstone Department of Molecular Microbiology and Immunology, The Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205
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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.
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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.
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Ding JW, Luo CY, Wang XA, Zhou T, Zheng XX, Zhang ZQ, Yu B, Zhang J, Tong XH. Glycyrrhizin, a High-Mobility Group Box 1 Inhibitor, Improves Lipid Metabolism and Suppresses Vascular Inflammation in Apolipoprotein E Knockout Mice. J Vasc Res 2019; 55:365-377. [DOI: 10.1159/000495310] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2018] [Accepted: 11/09/2018] [Indexed: 11/19/2022] Open
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Salami M, Kouchaki E, Asemi Z, Tamtaji OR. How probiotic bacteria influence the motor and mental behaviors as well as immunological and oxidative biomarkers in multiple sclerosis? A double blind clinical trial. J Funct Foods 2019. [DOI: 10.1016/j.jff.2018.10.023] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
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Denstaedt SJ, Singer BH, Standiford TJ. Sepsis and Nosocomial Infection: Patient Characteristics, Mechanisms, and Modulation. Front Immunol 2018; 9:2446. [PMID: 30459764 PMCID: PMC6232897 DOI: 10.3389/fimmu.2018.02446] [Citation(s) in RCA: 62] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2018] [Accepted: 10/03/2018] [Indexed: 12/16/2022] Open
Abstract
Sepsis is a leading cause of death worldwide. After initial trials modulating the hyperinflammatory phase of sepsis failed, generations of researchers have focused on evaluating hypo-inflammatory immune phenotypes. The main goal has been to develop prognostic biomarkers and therapies to reduce organ dysfunction, nosocomial infection, and death. The depressed host defense in sepsis has been characterized by broad cellular reprogramming including lymphocyte exhaustion, apoptosis, and depressed cytokine responses. Despite major advances in this field, our understanding of the dynamics of the septic host response and the balance of inflammatory and anti-inflammatory cellular programs remains limited. This review aims to summarize the epidemiology of nosocomial infections and characteristic immune responses associated with sepsis, as well as immunostimulatory therapies currently under clinical investigation.
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Affiliation(s)
| | | | - Theodore J. Standiford
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, United States
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Beringer A, Miossec P. IL-17 and IL-17-producing cells and liver diseases, with focus on autoimmune liver diseases. Autoimmun Rev 2018; 17:1176-1185. [PMID: 30321671 DOI: 10.1016/j.autrev.2018.06.008] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2018] [Accepted: 06/05/2018] [Indexed: 02/07/2023]
Abstract
The pro-inflammatory cytokine interleukin(IL)-17 and IL-17-producing cells are important players in the pathogenesis of many autoimmune / inflammatory diseases. More recently, they have been associated with liver diseases. This review first describes the general knowledge on IL-17 and IL-17 producing cells. The second part describes the in vitro and in vivo effects of IL-17 on liver cells and the contribution of IL-17 producing cells to liver diseases. IL-17 induces immune cell infiltration and liver damage driving to hepatic inflammation and fibrosis and contributes to autoimmune liver diseases. The circulating levels of IL-17 and the frequency of IL-17-producing cells are elevated in a variety of acute and chronic liver diseases. The last part focuses on the effects of IL-17 deletion or neutralization in various murine models. Some of these observed beneficial effects suggest that targeting the IL-17 axis could be a new therapeutic strategy to prevent chronicity and progression of various liver diseases.
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Affiliation(s)
- Audrey Beringer
- Immunogenomics and Inflammation Research Unit EA4130, University of Lyon, Lyon, France
| | - Pierre Miossec
- Immunogenomics and Inflammation Research Unit EA4130, University of Lyon, Lyon, France.
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Ding JW, Zhou T, Zheng XX, Wang XA, Tong XH, Luo CY, Zhang ZQ, Yu B. The Effects of High Mobility Group Box-1 Protein on Peripheral Treg/Th17 Balance in Patients with Atherosclerosis. ACTA CARDIOLOGICA SINICA 2018; 34:399-408. [PMID: 30271090 PMCID: PMC6160517 DOI: 10.6515/acs.201809_34(5).20180419a] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Subscribe] [Scholar Register] [Received: 11/11/2017] [Accepted: 04/19/2018] [Indexed: 11/23/2022]
Abstract
BACKGROUND Atherosclerosis (AS) is defined as chronic inflammation of the vessel wall. The major objective of the this study was to explore the mechanism of Treg/Th17 imbalance and the role of high mobility group box-1 protein (HMGB1) on the balance in AS. METHODS We detected the apoptotic ratios of Treg and Th17 cells in peripheral blood mononuclear cells (PBMCs) from subjects with AS and normal coronary arteries (NCA) by flow cytometry. The effects of recombinant HMGB1 (rHMGB1) on the proportion, apoptosis and differentiation of Treg and Th17 cells were analyzed using flow cytometry, qRT-PCR and ELISA. RESULTS The frequencies of apoptotic Treg cells in the PBMCs from the subjects with AS were significantly higher than in those with NCA (p < 0.01). Stimulation of rHMGB1 obviously increased the level of Th17 cells and acid- related orphan receptor C (RORC) mRNA, and markedly decreased Treg cell frequency and the mRNA expression of factor forkhead family protein 3 (Foxp3) in the PBMCs. rHMGB1 played an obvious role in elevating Treg cell apoptosis ratio (p < 0.01). rHMGB1 treatment significantly decreased Treg cell ratio and IL-10 level, and increased Th17 cell ratio and IL-17A level induced from naïve CD4+ T cells. CONCLUSIONS HMGB1 may modulate Treg/Th17 balance in patients with AS through inducing Treg cell apoptosis and promoting cell differentiation of Th17.
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Affiliation(s)
- Jia-Wang Ding
- Department of Cardiology, The First College of Clinical Medical Sciences, China Three Gorges University
- Institute of Cardiovascular Diseases, China Three Gorges University, Yichang 443000, Hubei Province, China
| | - Tian Zhou
- Department of Cardiology, The First College of Clinical Medical Sciences, China Three Gorges University
- Institute of Cardiovascular Diseases, China Three Gorges University, Yichang 443000, Hubei Province, China
| | - Xia-Xia Zheng
- Department of Cardiology, The First College of Clinical Medical Sciences, China Three Gorges University
- Institute of Cardiovascular Diseases, China Three Gorges University, Yichang 443000, Hubei Province, China
| | - Xin-An Wang
- Department of Cardiology, The First College of Clinical Medical Sciences, China Three Gorges University
- Institute of Cardiovascular Diseases, China Three Gorges University, Yichang 443000, Hubei Province, China
| | - Xiao-Hong Tong
- Department of Cardiology, The First College of Clinical Medical Sciences, China Three Gorges University
- Institute of Cardiovascular Diseases, China Three Gorges University, Yichang 443000, Hubei Province, China
| | - Cai-Yun Luo
- Department of Cardiology, The First College of Clinical Medical Sciences, China Three Gorges University
- Institute of Cardiovascular Diseases, China Three Gorges University, Yichang 443000, Hubei Province, China
| | - Zai-Qiang Zhang
- Department of Cardiology, The First College of Clinical Medical Sciences, China Three Gorges University
- Institute of Cardiovascular Diseases, China Three Gorges University, Yichang 443000, Hubei Province, China
| | - Bin Yu
- Department of Cardiology, The First College of Clinical Medical Sciences, China Three Gorges University
- Institute of Cardiovascular Diseases, China Three Gorges University, Yichang 443000, Hubei Province, China
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HMGB1-induced autophagy facilitates hepatic stellate cells activation: a new pathway in liver fibrosis. Clin Sci (Lond) 2018; 132:1645-1667. [PMID: 29907694 DOI: 10.1042/cs20180177] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2018] [Revised: 06/11/2018] [Accepted: 06/14/2018] [Indexed: 02/07/2023]
Abstract
High-mobility group box-1 (HMGB1) plays a context-dependent role in autophagy, which is required for hepatic stellate cells (HSCs) activation. However, the significance of HMGB1-induced HSCs autophagy in liver fibrosis has not been elucidated. Here, we first documented an enrichment of peripheral and intrahepatic HMGB1 signal in hepatitis B virus (HBV)-related liver fibrosis progression, and presented a direct evidence of anatomic proximity of HMGB1 with a-SMA (a marker for HSCs activation) in cirrhotic liver specimens. Then, we demonstrated the autophagy-inducing effects by serum-sourced HMGB1 in both primary murine HSCs and human HSCs cell line (LX-2), reflected by increased number of autophagic vacuoles (AVs) under the transmission electron microscope (TEM) and up-regulated protein expression of lipidated microtubule-associated light chain 3 (LC3-II) (a marker for autophagosome) in Western blot analysis. Intriguingly, there is a possible translocation of endogenous HMGB1 from the nucleus to cytoplasm to extracellular space, during exogenous HMGB1-induced HSCs autophagy. Meanwhile, the dose- and time-dependent effects by recombinant HMGB1 (rHMGB1) in enhancing LX-2 autophagy and fibrogenesis have been revealed with activated extracellular regulated protein kinase (ERK)/c-Jun N-terminal kinase (JNK) mitogen-activated protein kinase (MAPK) and restrained mammalian target of rapamycin (mTOR)/STAT3 signaling pathways. Additionally, the ERK or JNK inhibitor could not only inhibit rHMGB1-induced autophagy and fibrogenesis in LX-2 cells, but also restore the suppressed mTOR and STAT3 pathways. Furthermore, using LC3-siRNA transfected LX-2, we found HMGB1-induced fibrogenesis is dependent on its autophagy-inducing effects. Finally, we elucidated the involvement of extracellular HMGB1-receptor for advenced glycation end product (RAGE) axis and endogenous HMGB1 in exogenous HMGB1-induced effects. Our findings could open new perspectives in developing an antifibrotic therapy by targetting the HSCs autophagy.
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Li R, Wang J, Zhu F, Li R, Liu B, Xu W, He G, Cao H, Wang Y, Yang J. HMGB1 regulates T helper 2 and T helper17 cell differentiation both directly and indirectly in asthmatic mice. Mol Immunol 2018; 97:45-55. [PMID: 29567318 DOI: 10.1016/j.molimm.2018.02.014] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2017] [Revised: 02/12/2018] [Accepted: 02/19/2018] [Indexed: 12/15/2022]
Abstract
The Th (T helper) 2 response is characteristic of allergic asthma, and Th17 cells are involved in more severe asthma. Recent studies demonstrated that HMGB1 (High mobility group box 1 protein) regulates airway inflammation and the Th2, Th17 inflammatory response in asthma. HMGB1 can interact with Toll-like receptors (TLR) 2 and 4, and the receptor for advanced glycation end products (RAGE), activating the NF-κB (nuclear factor kappa B) signaling pathway and inducing the release of downstream inflammatory mediators. Both Th cells and dendritic cells express TLR2, TLR4, and RAGE receptors. Therefore, we speculate that HMGB1 could regulate the differentiation of Th2, Th17 cells in asthma through direct and indirect mechanisms. An ovalbumin (OVA)-induced mouse asthmatic model was established. Anti-HMGB1 antibody or rHMGB1 was administered to OVA-sensitized mice 30 min prior to each challenge. For in vitro studies, magnetically separated CD4+ naive T cells were stimulated with or without rHMGB1 and/or anti-HMGB1 antibody. BMDCs (bone marrow-derived dendritic cells)-stimulated with or without rHMGB1 and/or anti-HMGB1 antibody were cocultured with CD4+ naive T cells. Our study showed that administration of rHMGB1 aggravated airway inflammation and mucus production, and induced Th2, Th17 polarization in asthmatic mice, and that anti-HMGB1 antibody weakened characteristic features of asthma and blocked the Th2, Th17 inflammatory responses. HMGB1 could directly act on naive T cells to induce differentiation of Th2, Th17 cells in vitro through activating the TLR2, TLR4, RAGE-NF-κB signal pathway in CD4+ naive T cells. HMGB1 could also indirectly promote Th2, Th17 differentiation via activating the TLR2, TLR4, RAGE-NF-κB signal pathway in DCs to mediate their maturation and antigen-presenting ability in vitro.
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Affiliation(s)
- Ruiting Li
- Department of Respiratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, PR China
| | - Jing Wang
- Department of Intensive Care Unit, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, PR China
| | - Fangfang Zhu
- Department of Intensive Care Unit, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, PR China
| | - Ruifang Li
- Department of Neurology, Hubei Third People's Hospital, Wuhan, Hubei 430033, PR China
| | - Bing Liu
- Department of Respiratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, PR China
| | - Wenjuan Xu
- Department of Respiratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, PR China
| | - Guangzhen He
- Department of Respiratory Medicine, Taihe Hospital of Hubei University of Medicine, Shiyan, 442000, PR China
| | - Huan Cao
- Department of Respiratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, PR China
| | - Yimin Wang
- Department of Respiratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, PR China
| | - Jiong Yang
- Department of Respiratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, PR China.
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Quercetin protects mouse liver against triptolide-induced hepatic injury by restoring Th17/Treg balance through Tim-3 and TLR4-MyD88-NF-κB pathway. Int Immunopharmacol 2017; 53:73-82. [PMID: 29040945 DOI: 10.1016/j.intimp.2017.09.026] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2017] [Revised: 09/25/2017] [Accepted: 09/26/2017] [Indexed: 12/22/2022]
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Agbayani G, Wachholz K, Chattopadhyay A, Gurnani K, Murphy SP, Krishnan L. Modulation of Th17 and regulatory T-cell responses during murine pregnancy contributes to increased maternal susceptibility toSalmonellaTyphimurium infection. Am J Reprod Immunol 2017; 78. [DOI: 10.1111/aji.12742] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2017] [Accepted: 07/25/2017] [Indexed: 12/13/2022] Open
Affiliation(s)
- Gerard Agbayani
- Department of Biochemistry, Microbiology and Immunology; University of Ottawa; Ottawa ON Canada
- Division of Life Sciences; Human Health Therapeutics, National Research Council Canada; Ottawa ON Canada
| | - Kristina Wachholz
- Division of Life Sciences; Human Health Therapeutics, National Research Council Canada; Ottawa ON Canada
| | - Anindita Chattopadhyay
- Division of Life Sciences; Human Health Therapeutics, National Research Council Canada; Ottawa ON Canada
| | - Komal Gurnani
- Division of Life Sciences; Human Health Therapeutics, National Research Council Canada; Ottawa ON Canada
| | - Shawn P. Murphy
- Department of Obstetrics and Gynecology; University of Rochester; Rochester NY USA
- Department of Microbiology and Immunology; University of Rochester; Rochester NY USA
| | - Lakshmi Krishnan
- Department of Biochemistry, Microbiology and Immunology; University of Ottawa; Ottawa ON Canada
- Division of Life Sciences; Human Health Therapeutics, National Research Council Canada; Ottawa ON Canada
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Inkaya AC, Demir NA, Kolgelier S, Sumer S, Demir LS, Ural O, Pehlivan FS, Aslan M, Arpaci A. Is serum high-mobility group box 1 (HMGB-1) level correlated with liver fibrosis in chronic hepatitis B? Medicine (Baltimore) 2017; 96:e7547. [PMID: 28885322 PMCID: PMC6392731 DOI: 10.1097/md.0000000000007547] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2016] [Revised: 06/18/2017] [Accepted: 06/26/2017] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND High-mobility group box 1 (HMGB1), identified as an alarmin molecule, was shown to have a role in virus-triggered liver injury. We aimed to evaluate the association between serum levels of HMGB1 and liver fibrosis. METHOD This cross-sectional case-control study included 189 chronic hepatitis B (CHB) patients and 51 healthy controls. All patients underwent liver biopsy and modified Knodell scoring system used to determine the fibrosis level in CHB patients. Serum HMGB1 levels were determined with enzyme-linked immunosorbent assay (ELISA). RESULTS Mean serum HMGB1 levels of patients (58.1 ± 54.7) were found to be higher than those of the control group (7.1 ± 4.3) (P = .001). HMGB1 levels of patients with advanced-stage fibrosis (stage 4 and 5) were detected to be higher than those of patients with early-stage fibrosis (stage 1-3). However, this difference was not statistically significant (P > .05). Albumin levels of fibrosis 3 and 4 patients were lower than fibrosis 1 and 2 patients. ALT, HBV DNA, and AFP levels of fibrosis 5 patients were significantly higher than fibrosis 1 and 2 patients, and their platelet and albumin levels are lower than fibrosis 1 and 2 patients (P < .001). In a logistic regression model, fibrosis levels were correlated with ALT values and inversely correlated with albumin levels. CONCLUSION In this study, we demonstrated that serum HMGB1 levels increase in the early course of liver injury and this increase is not correlated with severity of the liver damage.
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Affiliation(s)
- Ahmet Cagkan Inkaya
- Department of Infectious Diseases and Clinical Microbiology, Faculty of Medicine, Hacettepe University, Ankara
| | - Nazlim Aktug Demir
- Department of Infectious Diseases and Clinical Microbiology, Faculty of Medicine, Selçuk University, Konya
| | - Servet Kolgelier
- Department of Infectious Diseases and Clinical Microbiology, Faculty of Medicine, Adiyaman University, Adiyaman
| | - Sua Sumer
- Department of Infectious Diseases and Clinical Microbiology, Faculty of Medicine, Selçuk University, Konya
| | - Lutfi Saltuk Demir
- Department of Public Health, Faculty of Medicine, Necmettin Erbakan University, Konya
| | - Onur Ural
- Department of Infectious Diseases and Clinical Microbiology, Faculty of Medicine, Selçuk University, Konya
| | | | - Mahmure Aslan
- Department of Biochemistry, Adiyaman Education and Research Hospital, Adiyaman
| | - Abdullah Arpaci
- Department of Biochemistry, Faculty of Medicine, Adiyaman University, Adiyaman, Turkey
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Bao S, Zheng J, Shi G. The role of T helper 17 cells in the pathogenesis of hepatitis B virus-related liver cirrhosis (Review). Mol Med Rep 2017; 16:3713-3719. [PMID: 28731149 PMCID: PMC5646947 DOI: 10.3892/mmr.2017.7044] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2016] [Accepted: 03/30/2017] [Indexed: 12/13/2022] Open
Abstract
In chronic hepatitis B virus (HBV)-infected patients, T helper 17 (Th17) cells are significantly elevated. Th17 cells initiate immune-mediated pathogenesis and have a critical role in the process of HBV-related liver cirrhosis (HBV-LC). The mechanisms underlying this process are attributed to Th17-secreted cytokines, which include interleukin (IL)-17, IL-21 and IL-22; however, a systemic analysis regarding these mechanisms has yet to be conducted. Therefore, the present study aimed to investigate the role of Th17 cells in the pathogenesis of HBV-LC. All randomized clinical trials, case series, case reports and meta-analyses that contained the aforementioned keywords were included in the review process. In addition, unpublished information from the Food and Drug Administration was included. The findings indicated that Th17-secreted cytokines, including IL-17, IL-21 and IL-22, function by activating or silencing hepatic stellate cells, modulating proinflammatory and pro- or antifibrogenic effectors, regulating extracellular matrix formation, upregulating chemokine expression, and inducing hepatocellular damage or hepatoprotection during the HBV-LC process. In addition, Th17 cells and Th17-secreted cytokines may be considered a potential tool in the diagnosis or treatment of HBV-LC. The present review summarized the role of Th17 cells in the pathogenesis of HBV-LC in order to deepen the clinical understanding of the role of Th17 cells and also to support the development of effective therapies for patients with HBV-LC.
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Affiliation(s)
- Suxia Bao
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China
| | - Jianming Zheng
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China
| | - Guangfeng Shi
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China
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Xu H, Wang L, Zheng P, Liu Y, Zhang C, Jiang K, Song H, Ji G. Elevated serum A20 is associated with severity of chronic hepatitis B and A20 inhibits NF-κB-mediated inflammatory response. Oncotarget 2017; 8:38914-38926. [PMID: 28473659 PMCID: PMC5503582 DOI: 10.18632/oncotarget.17153] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2017] [Accepted: 04/03/2017] [Indexed: 12/14/2022] Open
Abstract
A20 is a powerful suppressor for inflammatory response. This study aims to determine A20 level in patients with chronic hepatitis B (CHB), and analyze its association with the disease severity. The role of A20 in inflammatory response was further investigated in vivo and in vitro. Our results showed significantly higher A20 in both serum and liver tissues in CHB patients than in health controls. Serum A20 level was positively correlated with ALT, AST and TNF-α. To induce hepatitis with inflammation and liver injury, mice were injected intraperitoneally with D-galactosamine (D-GalN), resulting in rapid increase of A20 in serum and liver tissues. Consistently, HepG2 and Huh-7 cells exposed to Lipopolysaccharide (LPS) or D-GalN were promoted to express A20. Moreover, overexpression or knockdown of A20 inhibited or increased TNF-α secretion separately. A20 significantly reduced pro-inflammatory cytokines expression and down-regulated phospho-IκBα and phospho-p65 in both cells. In conclusion, elevated A20 expression is involved in the severity of CHB, suggesting A20 to be a possible serological biomarker for the disease prognosis. Additionally, the inflammatory response is attenuated by A20 through inhibiting NF-κB activity, which partially contributes to the hepato-protective function of this molecule. Thus, up-regulating A20 might be a potential strategy for preventing the progress of CHB.
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Affiliation(s)
- Hanchen Xu
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Lei Wang
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Peiyong Zheng
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
- China-Canada Centre of Research for Digestive Diseases, Shanghai 200032, China
| | - Yang Liu
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Chunlei Zhang
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Kaiping Jiang
- Department of Hepatology, Foshan Hospital of Traditional Chinese Medicine, Foshan 528000, China
| | - Haiyan Song
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
- China-Canada Centre of Research for Digestive Diseases, Shanghai 200032, China
| | - Guang Ji
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
- China-Canada Centre of Research for Digestive Diseases, Shanghai 200032, China
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Cheng LS, Li J, Liu Y, Wang FP, Wang SQ, She WM, Wu SD, Qi XL, Zhou YP, Jiang W. HMGB1-induced autophagy: a new pathway to maintain Treg function during chronic hepatitis B virus infection. Clin Sci (Lond) 2017; 131:381-394. [PMID: 28082516 DOI: 10.1042/cs20160704] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2016] [Revised: 12/29/2016] [Accepted: 01/12/2017] [Indexed: 01/13/2023]
Abstract
High-mobility group box-1 (HMGB1) protein, as one of the well-known damage-associated molecular pattern molecules (DAMPs), is enriched in chronic hepatitis B virus (HBV) infection and has a context-dependent role in autophagy, a highly conserved self-digestive process in response to environmental stress. Recent mouse studies indicate that autophagy is highly active in regulatory T (Treg)-cells. In the present study, we evaluated spontaneous and induced autophagy of peripheral Treg cells from 98 patients with chronic hepatitis B (CHB), by measuring levels of lipidated form of microtubule-associated light chain 3 (LC3-II, marker for closed autophagosomes) and observing autophagic vacuoles (AV) with transmission electron microscope. No significant difference was found in spontaneous autophagy of either Treg or CD4+ naive cells when comparing CHB patients with healthy subjects, apart from CHB-Treg showed significantly higher autophagic activity after activation by anti-CD3-CD28 beads. Besides, incubation of CHB-Treg cells with CHB-serum greatly maintained their autophagic behaviour, which could be significantly diminished by blocking HMGB1 with the neutralizing antibody. Further, we characterized time- and dose-dependent effects by recombinant HMGB1 protein on autophagy of CHB-Treg cells. We also documented a significant up-regulation of HMGB1 and its receptors [toll-like receptor (TLR4), receptor for advanced glycation end-product (RAGE)] in both peripheral and intra-hepatic microenvironments of CHB patients. Moreover, the RAGE-extracellular regulated protein kinases (ERK) axis and rapamycin-sensitive components of mammalian target of rapamycin (mTOR) pathways were demonstrated in vitro to be involved in HMGB1-induced autophagy of Treg cells. Additionally, HMGB1-induced autophagy could maintain cell survival and functional stability of CHB-Treg cells. Our findings could open new perspectives in developing therapeutic strategies to activate specific anti-HBV immunity by diminishing Treg autophagy.
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Affiliation(s)
- Li-Sha Cheng
- Department of Gastroenterology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jing Li
- Department of Gastroenterology, Tongji Hospital, Tongji University, Shanghai, China
| | - Yun Liu
- Department of Gastroenterology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Fu-Ping Wang
- Department of Gastroenterology, Children's Hospital, Capital Institute of Pediatrics, Beijing, China
| | - Si-Qi Wang
- Department of Gastroenterology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Wei-Min She
- Department of Gastroenterology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Sheng-di Wu
- Department of Gastroenterology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xiao-Long Qi
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yong-Ping Zhou
- Department of Hepatobiliary Surgery, Second People's Hospital, Nanjing Medical University, Wuxi, China
| | - Wei Jiang
- Department of Gastroenterology, Zhongshan Hospital, Fudan University, Shanghai, China
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Laursen TL, Støy S, Deleuran B, Vilstrup H, Grønbaek H, Sandahl TD. The damage-associated molecular pattern HMGB1 is elevated in human alcoholic hepatitis, but does not seem to be a primary driver of inflammation. APMIS 2016; 124:741-7. [DOI: 10.1111/apm.12568] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2016] [Accepted: 05/18/2016] [Indexed: 01/14/2023]
Affiliation(s)
- Tea Lund Laursen
- Department of Hepatology and Gastroenterology; Aarhus University Hospital; Aarhus Denmark
| | - Sidsel Støy
- Department of Hepatology and Gastroenterology; Aarhus University Hospital; Aarhus Denmark
| | - Bent Deleuran
- Department of Biomedicine; Aarhus University; Aarhus Denmark
| | - Hendrik Vilstrup
- Department of Hepatology and Gastroenterology; Aarhus University Hospital; Aarhus Denmark
| | - Henning Grønbaek
- Department of Hepatology and Gastroenterology; Aarhus University Hospital; Aarhus Denmark
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Ding JW, Zheng XX, Zhou T, Tong XH, Luo CY, Wang XA. HMGB1Modulates the Treg/Th17 Ratio in Atherosclerotic Patients. J Atheroscler Thromb 2016; 23:737-45. [PMID: 26830200 PMCID: PMC7399277 DOI: 10.5551/jat.31088] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2015] [Accepted: 11/16/2015] [Indexed: 01/14/2023] Open
Abstract
AIM Atherosclerosis (AS) characterized as a chronic inflammatory disease. Multiple immune cells and inflammatory cytokines, such as high mobility group protein (HMGB1), regulatory T (Treg) cells, T helper (Th17) cells, and inflammation-related cytokines, play a key role in its pathophysiology. A large number of studies report that HMGB1 and Th17 cells may promote atherosclerosis progression, whereas Treg cells may play a protective role in atherosclerosis; thus, alterations in the Treg/Th17 ratio may exist in atherosclerosis diseases. Up till now, the relationships between HMGB1 levels and the Treg/Th17 ratio remain incompletely understood. The major purpose of this study was to investigate the relationship between HMGB1 levels and the Treg/Th17 ratio in patients with coronary artery atherosclerotic plaques. METHODS We enrolled patients with coronary atherosclerosis and normal coronary artery as the research subjects. Flow cytometry was used to analyze the Treg cells, the Th17 cells frequency, and the Treg/Th17 ratio. Otherwise, real-time polymerase chain reaction was used for assays the mRNA expressions of HMGB1, retinoic acid-related orphan nuclear receptor C (RORC), and forkhead-winged helix transcription factor (Foxp3). Moreover, enzyme-linked immunosorbent assays were used to detect the level of protein and cytokines, such as HMGB1, IL-10, TGF-β1, IL-17A, and IL-23. RESULTS Using flow cytometry, we observed a significantly increased of Th17 cell frequency, whereas Treg cell frequency significantly decreased in atherosclerotic patients. Consistently, the levels of RORC mRNA were significantly increased in coronary atherosclerosis (AS) group compared to normal coronary artery (NCA) group (P＜0.01). In contrast, the expression of Foxp3 mRNA was markedly lower in the AS group than in the NCA group (P＜0.01). Furthermore, we observed the serum concentrations of HMGB1, IL-17A, and IL-23 were significantly higher in the AS group than in the NCA group (P＜0.01, respectively), whereas the concentrations of serum IL-10 and TGF-β1 were significantly lower in the AS group than in the NCA group (P＜0.01, respectively). In addition, we also found that HMGB1 levels showed negative correlation with the Treg/Th17 ratio in the two groups (r=－0.6984, P＜0.01). CONCLUSIONS The data in our study indicated that HMGB1 may promote atherosclerosis progression via modulating the imbalance in the Treg/Th17 ratio.
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Affiliation(s)
- Jia-wang Ding
- Department of Cardiology, the First College of Clinical Medical Sciences, China Three Gorges University, Hubei Province, China
- Institute of Cardiovascular Diseases, China Three Gorges University, Hubei Province, China
| | - Xia-xia Zheng
- Department of Cardiology, the First College of Clinical Medical Sciences, China Three Gorges University, Hubei Province, China
- Institute of Cardiovascular Diseases, China Three Gorges University, Hubei Province, China
| | - Tian Zhou
- Department of Cardiology, the First College of Clinical Medical Sciences, China Three Gorges University, Hubei Province, China
- Institute of Cardiovascular Diseases, China Three Gorges University, Hubei Province, China
| | - Xiao-hong Tong
- Department of Cardiology, the First College of Clinical Medical Sciences, China Three Gorges University, Hubei Province, China
- Institute of Cardiovascular Diseases, China Three Gorges University, Hubei Province, China
| | - Cai-yun Luo
- Department of Cardiology, the First College of Clinical Medical Sciences, China Three Gorges University, Hubei Province, China
- Institute of Cardiovascular Diseases, China Three Gorges University, Hubei Province, China
| | - Xin-an Wang
- Department of Cardiology, the First College of Clinical Medical Sciences, China Three Gorges University, Hubei Province, China
- Institute of Cardiovascular Diseases, China Three Gorges University, Hubei Province, China
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Yu X, Zheng Y, Deng Y, Li J, Guo R, Su M, Ming D, Lin Z, Zhang J, Su Z. Serum Interleukin (IL)-9 and IL-10, but not T-Helper 9 (Th9) Cells, are Associated With Survival of Patients With Acute-on-Chronic Hepatitis B Liver Failure. Medicine (Baltimore) 2016; 95:e3405. [PMID: 27100428 PMCID: PMC4845832 DOI: 10.1097/md.0000000000003405] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/26/2023] Open
Abstract
CD4 T helper (Th) cells are reported to be essential for initiating and maintaining an effective immune response to hepatitis B virus (HBV) infection. Th9 cells are a new subset of CD4 Th cells that produce interleukin (IL)-9 and IL-10. The present study aimed to investigate the percentage of Th9 cells relative to the number of CD4 cells in peripheral blood. We also measured serum IL-9 and IL-10 levels in different stages of HBV infection and their relationship with progress and prognosis of liver disease. Whole blood samples from 111 patients with HBV infection, including 39 chronic hepatitis B (CHB), 25 HBV-liver cirrhosis (HBV-LC), 21 acute-on-chronic liver failure (ACLF) patients, and 26 healthy controls were collected. The percentage of Th9 cells and serum IL-9 and IL-10 levels were determined. There was no significant difference in the percentage of Th9 cells and serum IL-9 and IL-10 levels among different groups, nor were these related to hepatitis B e antigen status, complications of cirrhosis, inflammation index, or prognosis indexes. There was no change in the percentage of Th9 cells before and after antiviral treatment in CHB patients. There was no correlation of Th9 cells with survival of ACLF patients. However, IL-9 and IL-10 levels were significantly higher in the nonsurvived ACLF patients compared to survived ACLF patients. Furthermore, baseline IL-9 level predicted the prognosis of ACLF patients with 87.5% sensitivity and 61.5% specificity.Thus, our data indicate that Th9 cells were unlikely involved in the pathogenesis of HBV infection, but elevation in IL-9 and IL-10 may signal poor prognosis for ACLF.
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Affiliation(s)
- Xueping Yu
- From the Department of Infectious Diseases and Clinical Laboratory (XY, YZ, JL, RG, MS, DM, ZL, ZS), the First Hospital of Quanzhou Affiliated to Fujian Medical University, Quanzhou; Department of Infectious Diseases (YD), the Second People's Hospital of Pingxiang, Pingxiang; and Department of Infectious Diseases (XY, JZ), Huashan Hospital, Fudan University, Shanghai, China
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