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Li H, Yu K, Zhang X, Li J, Hu H, Deng X, Zeng S, Dong X, Zhao J, Zhang Y. YTHDF1 shapes immune-mediated hepatitis via regulating inflammatory cell recruitment and response. Genes Dis 2025; 12:101327. [PMID: 40092485 PMCID: PMC11910365 DOI: 10.1016/j.gendis.2024.101327] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Revised: 03/07/2024] [Accepted: 03/31/2024] [Indexed: 03/19/2025] Open
Abstract
Severe immune responses regulate the various clinical hepatic injuries, including autoimmune hepatitis and acute viral hepatitis. N6-methyladenosine (m6A) modification is a crucial regulator of immunity and inflammation. However, the precise role of YTHDF1 in T cell-mediated hepatitis remains incompletely characterized. To address this, we utilized Concanavalin A (ConA)-induced mouse liver damage as an experimental model for T cell-mediated hepatitis. Our findings found that hepatic YTHDF1 protein rapidly decreased during ConA-induced hepatitis, and YTHDF1-deficient (Ythdf1 -/- ) mice showed more susceptibility to ConA-induced liver injury, along with an intensified inflammatory storm accompanied by aggravated hepatic inflammatory response via ERK and NF-κB pathways. Interestingly, hepatic-specific over-expression or deletion of YTHDF1 exhibited redundancy in ConA-induced liver injury. Validation in bone marrow chimeric mice confirmed the necessity of YTHDF1 in hematopoietic cells for controlling the response to ConA-induced hepatitis. Additionally, our data revealed that YTHDF1 deletion in macrophages exacerbated the inflammatory response induced by lipopolysaccharide. In summary, our study uncovered that YTHDF1 deficiency exacerbates the immune response in ConA-induced hepatitis by modulating the expression of inflammatory mediators, highlighting the potential of YTHDF1 as a therapeutic target for clinical hepatitis.
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Affiliation(s)
- Hao Li
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China
| | - Kailun Yu
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China
| | - Xiandan Zhang
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China
| | - Jiawen Li
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China
- School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian 361102, China
| | - Huilong Hu
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China
| | - Xusheng Deng
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China
| | - Siyu Zeng
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China
| | - Xiaoning Dong
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China
- School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian 361102, China
| | - Junru Zhao
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China
| | - Yongyou Zhang
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China
- National Institute for Data Science in Health and Medicine Engineering, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, China
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Fu H, Wang X, Yuan M, Wang N, Zhang X. Callistephus A from Callistephus chinensis Nees alleviates concanavalin A-induced immunological liver injury in mice by inhibiting the activation of JAK/STAT1 and MAPK signaling pathways. Int Immunopharmacol 2025; 148:114153. [PMID: 39864226 DOI: 10.1016/j.intimp.2025.114153] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Revised: 11/07/2024] [Accepted: 01/21/2025] [Indexed: 01/28/2025]
Abstract
Callistephus chinensis Nees is an herbaceous plant in the Asteraceae family that has various traditional effects, especially in preventing liver disease. Callistephus A (CA) is a sesquiterpene compound with a rare 6/7 ring skeleton, which has been isolated only from the Callistephus chinensis Nees, but whether CA protects the liver is unknown. Immunological liver injury (ILI) is a common liver disease mediated by the immune system. Therefore, this study investigated whether CA had a protective effect on ILI and uncovered its molecular mechanisms. To study the impact, target, and signal pathway of CA in preventing ILI, we hope to find active components from plants to avoid ILI. In this study, CA regulated the differentiation balance of CD4 + T cells (Th1/Th2 and Th17/Treg balance) and the secretion of inflammatory factors (tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), interferon-gamma (IFN-γ), interleukin-4 (IL-4), interleukin-17A (IL-17A) and transforming growth factor-β (TGF-β). CA improves liver inflammation by regulating IFN-γ-induced JAK/STAT1 signaling pathways. CA reduced hepatocyte apoptosis by decreasing protein expression of BCL2-associated X (Bax), cleaved caspase-3, and cleaved Poly (ADP-ribose) polymerase 1 (PARP-1), but increased Bcl-2 protein expression, which was achieved by regulating the MAPK pathway. To investigate the role of CA in immune liver injury, we performed in vitro cell experiments using alpha mouse liver 12 (AML12) cells. The cell experiments showed that CA potently inhibited LPS-mediated AML12 cell damage. After adding CA, damaged mitochondria are cleared through mitochondrial autophagy and reduced production of intracellular reactive oxygen species (ROS). Finally, molecular docking results showed that CA had a strong affinity for five essential target proteins (JAK1, JAK2, STAT1, JNK, and p38). CA regulates the differentiation, anti-inflammatory, and anti-apoptosis of CD4 + T cells. The mechanism of CA against ILI is related to inhibiting the activation of JAK/STAT1 and MAPK signaling pathways.
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Affiliation(s)
- Haonan Fu
- School of Functional Food and Wine, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China
| | - Xiaojun Wang
- School of Functional Food and Wine, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China
| | - Mingyuan Yuan
- School of Functional Food and Wine, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China
| | - Ning Wang
- School of Functional Food and Wine, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China
| | - Xiaoshu Zhang
- School of Functional Food and Wine, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China.
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Lin CI, Wang YW, Su KY, Chuang YH. Interleukin-37 exacerbates liver inflammation and promotes IFN-γ production in NK cells. Int Immunopharmacol 2024; 142:113086. [PMID: 39260304 DOI: 10.1016/j.intimp.2024.113086] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Revised: 08/23/2024] [Accepted: 09/02/2024] [Indexed: 09/13/2024]
Abstract
Interleukin (IL)-37, a unique member of the IL-1 family, is known for its anti-inflammatory properties. However, its effects on immune-mediated liver diseases, such as primary biliary cholangitis (PBC) and acute immune-mediated hepatitis, remain unclear. Using mouse models of autoimmune cholangitis and hepatitis induced by 2-OA-OVA and concanavalin A (Con A) respectively, we introduced the human IL-37 gene via a liver-preferred adeno-associated virus vector (AAV-IL-37) to mice, as mice lack endogenous IL-37. Our findings reveal that IL-37 did not affect autoimmune cholangitis. Surprisingly, IL-37 exacerbated inflammation in Con A-induced hepatitis rather than mitigating it. Mechanistic insights suggest that this exacerbation involves the interferon (IFN)-γ pathway, supported by elevated serum IFN-γ levels in AAV-IL-37-treated Con A mice. Specifically, IL-37 heightened the number of hepatic NK and NKT cells, increased the production of the NK cell chemoattractant CCL5, and elevated the frequency of hepatic NK and NKT cells expressing IFN-γ. Moreover, IL-37 enhanced IFN-γ secretion from NK cells when combined with other proinflammatory cytokines, highlighting its synergistic effect in promoting IFN-γ production. These unexpected outcomes underscore a novel role for IL-37 in exacerbating liver inflammation during immune-mediated liver diseases, implicating its influence on NK cells and the production of IFN-γ by these cells.
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Affiliation(s)
- Chia-I Lin
- Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Yu-Wen Wang
- Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Kang-Yi Su
- Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan; Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan; Genomic and Systems Biology Degree Program, National Taiwan University and Academia Sinica, Taipei, Taiwan
| | - Ya-Hui Chuang
- Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan; Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan.
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Nabekura T, Matsuo S, Shibuya A. Concanavalin-A-Induced Acute Liver Injury in Mice. Curr Protoc 2024; 4:e1117. [PMID: 39126326 DOI: 10.1002/cpz1.1117] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/12/2024]
Abstract
Acute liver injury is a life-threatening disease. Although immune responses are involved in the development and exacerbation of acute liver injury, the cellular and molecular mechanisms are not fully understood. Intravenous administration of the plant lectin concanavalin A (ConA) is widely used as a model of acute liver injury. ConA triggers T cell activation and cytokine production by crosslinking glycoproteins, including the T cell receptor, leading to the infiltration of myeloid cells into the liver and the subsequent amplification of inflammation in the liver. Thus, the pathogenesis of ConA-induced acute liver injury is considered a model of immune-mediated acute liver injury or autoimmune hepatitis in humans. However, the severity of the liver injury and the analyses of immune cells and non-hematopoietic cells in the liver following ConA injection are significantly influenced by the experimental conditions. This article outlines protocols for ConA-induced acute liver injury in mice and evaluation methods for liver injury, immune cells, and non-hematopoietic cells in the liver. © 2024 Wiley Periodicals LLC. Basic Protocol 1: Induction of acute liver injury by ConA injection Basic Protocol 2: Evaluation of inflammatory cytokines in mouse plasma Basic Protocol 3: Preparation of liver sections and histological analysis of liver injury Basic Protocol 4: Preparation of liver immune cells Basic Protocol 5: Preparation of hepatocytes, endothelial cells, and hepatic stellate cells Basic Protocol 6: Flow cytometry of immune and non-hematopoietic liver cells Basic Protocol 7: Flow cytometric sorting of endothelial cells and hepatic stellate cells Basic Protocol 8: Quantitative reverse transcription polymerase chain reaction.
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Affiliation(s)
- Tsukasa Nabekura
- Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, Tsukuba, Ibaraki, Japan
- R&D Center for Innovative Drug Discovery, University of Tsukuba, Tsukuba, Ibaraki, Japan
- Division of Immune Response, Aichi Cancer Center Research Institute, Nagoya, Aichi, Japan
| | - Soichi Matsuo
- Department of Immunology, Institute of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
- Doctoral Program in Medical Science, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan
- Department of Advanced Medical Technologies, National Cerebral and Vascular Cancer Center Research Institute, Suita, Osaka, Japan
| | - Akira Shibuya
- Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, Tsukuba, Ibaraki, Japan
- R&D Center for Innovative Drug Discovery, University of Tsukuba, Tsukuba, Ibaraki, Japan
- Department of Immunology, Institute of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
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Kurokawa M, Goya T, Kohjima M, Tanaka M, Iwabuchi S, Shichino S, Ueha S, Hioki T, Aoyagi T, Takahashi M, Imoto K, Tashiro S, Suzuki H, Kato M, Hashimoto S, Matsuda H, Matsushima K, Ogawa Y. Microcirculatory disturbance in acute liver injury is triggered by IFNγ-CD40 axis. J Inflamm (Lond) 2024; 21:23. [PMID: 38907339 PMCID: PMC11191181 DOI: 10.1186/s12950-024-00387-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Accepted: 04/15/2024] [Indexed: 06/23/2024] Open
Abstract
BACKGROUND Acute liver failure (ALF) is a life-threatening disorder that progresses from self-limiting acute liver injury (ALI). Microcirculatory disturbance characterized by sinusoidal hypercoagulation and subsequent massive hypoxic hepatocyte damage have been proposed to be the mechanism by which ALI deteriorates to ALF; however, the precise molecular pathway of the sinusoidal hypercoagulation remains unknown. Here, we analyzed ALI patients and mice models to uncover the pathogenesis of ALI with microcirculatory disturbance. METHODS We conducted a single-center retrospective study for ALI and blood samples and liver tissues were analyzed to evaluate the microcirculatory disturbance in ALI patients (n = 120). Single-cell RNA sequencing analysis (scRNA-seq) was applied to the liver from the concanavalin A (Con A)‑induced mouse model of ALI. Interferon-gamma (IFNγ) and tumor necrosis factor-alpha knockout mice, and primary human liver sinusoidal endothelial cells (LSECs) were used to assess the mechanism of microcirculatory disturbance. RESULTS The serum IFNγ concentrations were significantly higher in ALI patients with microcirculatory disturbance than in patients without microcirculatory disturbance, and the IFNγ was upregulated in the Con A mouse model which presented microcirculatory disturbance. Hepatic IFNγ expression was increased as early as 1 hour after Con A treatment prior to sinusoidal hypercoagulation and hypoxic liver damage. scRNA-seq revealed that IFNγ was upregulated in innate lymphoid cells and stimulated hepatic vascular endothelial cells at the early stage of liver injury. In IFNγ knockout mice treated with Con A, the sinusoidal hypercoagulation and liver damage were remarkably attenuated, concomitant with the complete inhibition of CD40 and tissue factor (TF) upregulation in vascular endothelial cells. By ligand-receptor analysis, CD40-CD40 ligand interaction was identified in vascular endothelial cells. In human LSECs, IFNγ upregulated CD40 expression and TF was further induced by increased CD40-CD40 ligand interaction. Consistent with these findings, hepatic CD40 expression was significantly elevated in human ALI patients with microcirculatory disturbance. CONCLUSION We identified the critical role of the IFNγ-CD40 axis as the molecular mechanism of microcirculatory disturbance in ALI. This finding may provide novel insights into the pathogenesis of ALI and potentially contribute to the emergence of new therapeutic strategies for ALI patients.
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Affiliation(s)
- Miho Kurokawa
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
- Department of Gastroenterology and Hepatology, NHO Fukuokahigashi Medical Center, 1-1-1 Chidori, Koga, 811-3195, Japan
| | - Takeshi Goya
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Motoyuki Kohjima
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
- Department of Gastroenterology, NHO Kyushu Medical Center, 1-8-1 Jigyohama, Chuo-ku, Fukuoka, 810-8563, Japan.
| | - Masatake Tanaka
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Sadahiro Iwabuchi
- Department of Molecular Pathophysiology, Institute of Advanced Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama-shi, 641-8509, Japan
| | - Shigeyuki Shichino
- Division of Molecular Regulation of Inflammatory and Immune Diseases, Research Institute for Biomedical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, 278-8510, Japan
| | - Satoshi Ueha
- Division of Molecular Regulation of Inflammatory and Immune Diseases, Research Institute for Biomedical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, 278-8510, Japan
| | - Tomonobu Hioki
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Tomomi Aoyagi
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Motoi Takahashi
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Koji Imoto
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Shigeki Tashiro
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Hideo Suzuki
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Masaki Kato
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
- Graduate School of Nutritional Sciences, Nakamura Gakuen University, 5-7-1 Befu, Jounan-ku, Fukuoka, 814-0198, Japan
| | - Shinichi Hashimoto
- Department of Molecular Pathophysiology, Institute of Advanced Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama-shi, 641-8509, Japan
| | - Hideo Matsuda
- Department of Bioinformatic Engineering, Graduate School of Information Science and Technology, Osaka University, 1-5 Yamadaoka, Suita-shi, 565-0871, Japan
| | - Kouji Matsushima
- Division of Molecular Regulation of Inflammatory and Immune Diseases, Research Institute for Biomedical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, 278-8510, Japan
| | - Yoshihiro Ogawa
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
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Kim JW, Kim YJ. The evidence-based multifaceted roles of hepatic stellate cells in liver diseases: A concise review. Life Sci 2024; 344:122547. [PMID: 38460810 DOI: 10.1016/j.lfs.2024.122547] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2023] [Revised: 02/21/2024] [Accepted: 03/04/2024] [Indexed: 03/11/2024]
Abstract
Hepatic stellate cells (HSCs) play central roles in liver disease pathogenesis, spanning steatosis to cirrhosis and hepatocellular carcinoma. These cells, located in the liver's sinusoidal space of Disse, transition from a quiescent, vitamin A-rich state to an activated, myofibroblast-like phenotype in response to liver injury. This activation results from a complex interplay of cytokines, growth factors, and oxidative stress, leading to excessive collagen deposition and liver fibrosis, a hallmark of chronic liver diseases. Recently, HSCs have gained recognition for their dynamic, multifaceted roles in liver health and disease. Attention has shifted toward their involvement in various liver conditions, including acute liver injury, alcoholic and non-alcoholic fatty liver disease, and liver regeneration. This review aims to explore diverse functions of HSCs in these acute or chronic liver pathologies, with a focus on their roles beyond fibrogenesis. HSCs exhibit a wide range of actions, including lipid storage, immunomodulation, and interactions with other hepatic and extrahepatic cells, making them pivotal in the hepatic microenvironment. Understanding HSC involvement in the progression of liver diseases can offer novel insights into pathogenic mechanisms and guide targeted therapeutic strategies for various liver conditions.
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Affiliation(s)
- Jong-Won Kim
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Yu Ji Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Medical School, Jeonbuk National University, Research Institute of Clinical Medicine of Jeonbuk National University - Biomedical Research Institute of Jeonbuk National University Hospital, Jeonju, South Korea.
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Wachtendorf S, Jonin F, Ochel A, Heinrich F, Westendorf AM, Tiegs G, Neumann K. The ST2 + Treg/amphiregulin axis protects from immune-mediated hepatitis. Front Immunol 2024; 15:1351405. [PMID: 38571949 PMCID: PMC10987816 DOI: 10.3389/fimmu.2024.1351405] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Accepted: 02/29/2024] [Indexed: 04/05/2024] Open
Abstract
Introduction The alarmin IL-33 has been implicated in the pathology of immune-mediated liver diseases. IL-33 activates regulatory T cells (Tregs) and type 2 innate lymphoid cells (ILC2s) expressing the IL-33 receptor ST2. We have previously shown that endogenous IL-33/ST2 signaling activates ILC2s that aggravate liver injury in murine immune-mediated hepatitis. However, treatment of mice with exogenous IL-33 before induction of hepatitis ameliorated disease severity. Since IL-33 induces expression of amphiregulin (AREG) crucial for Treg function, we investigated the immunoregulatory role of the ST2+ Treg/AREG axis in immune-mediated hepatitis. Methods C57BL/6, ST2-deficient (Il1rl1-/-) and Areg-/- mice received concanavalin A to induce immune-mediated hepatitis. Foxp3Cre+ x ST2fl/fl mice were pre-treated with IL-33 before induction of immune-mediated hepatitis. Treg function was assessed by adoptive transfer experiments and suppression assays. The effects of AREG and IL-33 on ST2+ Tregs and ILC2s were investigated in vitro. Immune cell phenotype was analyzed by flow cytometry. Results and discussion We identified IL-33-responsive ST2+ Tregs as an effector Treg subset in the murine liver, which was highly activated in immune-mediated hepatitis. Lack of endogenous IL-33 signaling in Il1rl1-/- mice aggravated disease pathology. This was associated with reduced Treg activation. Adoptive transfer of exogenous IL-33-activated ST2+ Tregs before induction of hepatitis suppressed inflammatory T-cell responses and ameliorated disease pathology. We further showed increased expression of AREG by hepatic ST2+ Tregs and ILC2s in immune-mediated hepatitis. Areg-/- mice developed more severe liver injury, which was associated with enhanced ILC2 activation and less ST2+ Tregs in the inflamed liver. Exogenous AREG suppressed ILC2 cytokine expression and enhanced ST2+ Treg activation in vitro. In addition, Tregs from Areg-/- mice were impaired in their capacity to suppress CD4+ T-cell activation in vitro. Moreover, application of exogenous IL-33 before disease induction did not protect Foxp3Cre+ x ST2fl/fl mice lacking ST2+ Tregs from immune-mediated hepatitis. In summary, we describe an immunoregulatory role of the ST2+ Treg/AREG axis in immune-mediated hepatitis, in which AREG suppresses the activation of hepatic ILC2s while maintaining ST2+ Tregs and reinforcing their immunosuppressive capacity in liver inflammation.
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Affiliation(s)
- Selina Wachtendorf
- Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Hamburg Center for Translational Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Fitriasari Jonin
- Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Hamburg Center for Translational Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Aaron Ochel
- Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Fabian Heinrich
- Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Astrid M. Westendorf
- Institute of Medical Microbiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Gisa Tiegs
- Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Hamburg Center for Translational Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Katrin Neumann
- Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Hamburg Center for Translational Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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8
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Saimaier K, Han S, Lv J, Zhuang W, Xie L, Liu G, Wang C, Zhang R, Hua Q, Shi C, Du C. Manganese Exacerbates ConA-Induced Liver Inflammation via the cGAS-STING Signaling Pathway. Inflammation 2024; 47:333-345. [PMID: 37805951 DOI: 10.1007/s10753-023-01912-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Revised: 09/21/2023] [Accepted: 09/22/2023] [Indexed: 10/10/2023]
Abstract
There is a potential association between the dysregulation of trace elements and impaired liver function. Elevated levels of manganese, an essential metal ion, have been observed in liver-related diseases, and excessive intake of manganese can worsen liver damage. However, the specific mechanisms underlying manganese-induced liver injury are not well understood. The aim of our study was to investigate the effects of excess manganese on autoimmune hepatitis (AIH) and elucidate its mechanisms. Our findings revealed that manganese exacerbates liver damage under ConA-induced inflammatory conditions. Transcriptomic and experimental data suggested that manganese enhances inflammatory signaling and contributes to the inflammatory microenvironment in the liver of AIH mice. Further investigations demonstrated that manganese exacerbates liver injury by activating the cGAS-STING signaling pathway and its downstream pro-inflammatory factors such as IFN[Formula: see text], IFN[Formula: see text], TNF[Formula: see text], and IL-6 in the liver of AIH mice. These results suggest that manganese overload promotes the progression of AIH by activating cGAS-STING-mediated inflammation, providing a new perspective for the treatment and prognosis of AIH.
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Affiliation(s)
- Kaidireya Saimaier
- Putuo People's Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Sanxing Han
- Putuo People's Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Jie Lv
- Putuo People's Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Wei Zhuang
- Putuo People's Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, China
- Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
- College of Life Sciences, University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Ling Xie
- Putuo People's Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Guangyu Liu
- Putuo People's Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Chun Wang
- Putuo People's Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Ru Zhang
- Putuo People's Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Qiuhong Hua
- Putuo People's Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Changjie Shi
- Putuo People's Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Changsheng Du
- Putuo People's Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, China.
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Meng C, Liu Y, Ming Y, Lu C, Li Y, Zhang Y, Su D, Gao X, Yuan Q. Enhancing Liver Delivery of Gold Nanoclusters via Human Serum Albumin Encapsulation for Autoimmune Hepatitis Alleviation. Pharmaceutics 2024; 16:110. [PMID: 38258120 PMCID: PMC10818704 DOI: 10.3390/pharmaceutics16010110] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Revised: 01/06/2024] [Accepted: 01/11/2024] [Indexed: 01/24/2024] Open
Abstract
Peptide-protected gold nanoclusters (AuNCs), possessing exceptional biocompatibility and remarkable physicochemical properties, have demonstrated intrinsic pharmaceutical activity in immunomodulation, making them a highly attractive frontier in the field of nanomedicine exploration. Autoimmune hepatitis (AIH) is a serious autoimmune liver disease caused by the disruption of immune balance, for which effective treatment options are still lacking. In this study, we initially identified glutathione (GSH)-protected AuNCs as a promising nanodrug candidate for AIH alleviating in a Concanavalin A (Con A)-induced mice model. However, to enhance treatment efficiency, liver-targeted delivery needs to be improved. Therefore, human serum albumin (HSA)-encapsulated AuNCs were constructed to achieve enhanced liver targeting and more potent mitigation of Con A-induced elevations in plasma aspartate transaminase (AST), alanine transaminase (ALT), and liver injury in mice. In vivo and in vitro mechanism studies indicated that AuNCs could suppress the secretion of IFN-γ by Con A-stimulated T cells and subsequently inhibit the activation of the JAK2/STAT1 pathway and eventual hepatocyte apoptosis induced by IFN-γ. These actions ultimately protect the liver from immune cell infiltration and damage caused by Con A. These findings suggest that bio-protected AuNCs hold promise as nanodrugs for AIH therapy, with their liver targeting capabilities and therapeutic efficiency being further improved via rational surface ligand engineering.
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Affiliation(s)
- Cong Meng
- Center of Excellence for Environmental Safety and Biological Effects, Beijing Key Laboratory for Green Catalysis and Separation, Department of Chemistry, Beijing University of Technology, Beijing 100124, China; (C.M.); (Y.M.); (C.L.); (Y.L.); (Y.Z.); (X.G.)
| | - Yu Liu
- College of Biological and Chemical Engineering, Qilu Institute of Technology, Jinan 250200, China;
| | - Yuping Ming
- Center of Excellence for Environmental Safety and Biological Effects, Beijing Key Laboratory for Green Catalysis and Separation, Department of Chemistry, Beijing University of Technology, Beijing 100124, China; (C.M.); (Y.M.); (C.L.); (Y.L.); (Y.Z.); (X.G.)
| | - Cao Lu
- Center of Excellence for Environmental Safety and Biological Effects, Beijing Key Laboratory for Green Catalysis and Separation, Department of Chemistry, Beijing University of Technology, Beijing 100124, China; (C.M.); (Y.M.); (C.L.); (Y.L.); (Y.Z.); (X.G.)
| | - Yanggege Li
- Center of Excellence for Environmental Safety and Biological Effects, Beijing Key Laboratory for Green Catalysis and Separation, Department of Chemistry, Beijing University of Technology, Beijing 100124, China; (C.M.); (Y.M.); (C.L.); (Y.L.); (Y.Z.); (X.G.)
| | - Yulu Zhang
- Center of Excellence for Environmental Safety and Biological Effects, Beijing Key Laboratory for Green Catalysis and Separation, Department of Chemistry, Beijing University of Technology, Beijing 100124, China; (C.M.); (Y.M.); (C.L.); (Y.L.); (Y.Z.); (X.G.)
| | - Dongdong Su
- Center of Excellence for Environmental Safety and Biological Effects, Beijing Key Laboratory for Green Catalysis and Separation, Department of Chemistry, Beijing University of Technology, Beijing 100124, China; (C.M.); (Y.M.); (C.L.); (Y.L.); (Y.Z.); (X.G.)
| | - Xueyun Gao
- Center of Excellence for Environmental Safety and Biological Effects, Beijing Key Laboratory for Green Catalysis and Separation, Department of Chemistry, Beijing University of Technology, Beijing 100124, China; (C.M.); (Y.M.); (C.L.); (Y.L.); (Y.Z.); (X.G.)
| | - Qing Yuan
- Center of Excellence for Environmental Safety and Biological Effects, Beijing Key Laboratory for Green Catalysis and Separation, Department of Chemistry, Beijing University of Technology, Beijing 100124, China; (C.M.); (Y.M.); (C.L.); (Y.L.); (Y.Z.); (X.G.)
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10
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Haikal A, Galala AA, Elshal M, Amen Y, Gohar AA. Bioactivity of Eriocephalus africanus essential oil against concanavalin A-induced hepatitis via suppressing immune cell infiltration, inhibiting TNF-α/NF-κB and IFN-γ/STAT1 signaling pathways. JOURNAL OF ETHNOPHARMACOLOGY 2024; 318:117000. [PMID: 37544345 DOI: 10.1016/j.jep.2023.117000] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/07/2023] [Revised: 07/26/2023] [Accepted: 08/02/2023] [Indexed: 08/08/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Eriocephalus africanus infusion is used as a diuretic and a diaphoretic and is also used in the treatment of gastrointestinal disorders and gynaecological conditions, inflammation and dermal disorders, asthma, coughs, fevers, and painful ailments. The plant has been used traditionally as a medication to cure inflammation and skin problems. AIM OF THE STUDY Studying E. africanus essential oil (EAEO) as a potential hepatoprotective measure against concanavalin (Con) A-induced hepatitis in mice and investigating its underlying mechanism. MATERIALS AND METHODS Hydro-distilled oil of the fresh plant aerial shoots is subjected to GC/MS analysis. Autoimmune hepatitis (AIH) was induced in mice by intravenous injection of Con A (15 mg/kg). EAEO was administered orally before Con A injection to test its hepatoprotective activity. RESULTS GC/MS analysis revealed the presence of 22 compounds representing 99.43% of the oil components. The monoterpene artemisia ketone (41.02%) and the sesquiterpene juniper camphor (14.17%) are the major components. The in vivo study showed that the oil suppressed Con A-induced neutrophil and CD4+T cell infiltration into the liver, restored hepatic redox balance, inhibited Con A-induced elevation of tumor necrosis factor-alpha (TNF-α), interleukin (IL-6), and interferon-gamma (IFN-γ) hepatic levels which were correlated with its ability to suppress nuclear factor kappa B (NF-κB) and Signal Transducer and Activator of Transcription (STAT1) activation in the liver. CONCLUSION EAEO showed hepatoprotective potential against Con A-induced hepatitis in mice collectively through selective anti-oxidant, anti-inflammatory, and anti-necrotic effects.
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Affiliation(s)
- Abdullah Haikal
- Department of Pharmacognosy, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt.
| | - Amal A Galala
- Department of Pharmacognosy, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt.
| | - Mahmoud Elshal
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt.
| | - Yhiya Amen
- Department of Pharmacognosy, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt.
| | - Ahmed A Gohar
- Department of Pharmacognosy, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt.
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Wang C, Han M, Li X, Lv J, Zhuang W, Xie L, Liu G, Saimaier K, Han S, Shi C, Hua Q, Zhang R, Jiang X, Wang G, Du C. TPN10475 alleviates concanavalin A-induced autoimmune hepatitis by limiting T cell development and function through inhibition of PI3K-AKT pathway. Int Immunopharmacol 2023; 125:111110. [PMID: 37883813 DOI: 10.1016/j.intimp.2023.111110] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Revised: 10/15/2023] [Accepted: 10/19/2023] [Indexed: 10/28/2023]
Abstract
Autoimmune hepatitis (AIH) is an inflammatory liver disease in which the autoimmune system instigates an attack on the liver, causing inflammation and liver injury, and its incidence has increased worldwide in recent years. The mouse model of acute hepatitis established by concanavalin A (Con A) is a typical and recognized mouse model for the study of T-cell-dependent liver injury. In this study, we aimed to investigate whether the artemisinin derivative TPN10475 could alleviate AIH and its possible mechanisms. TPN10475 effectively inhibited lymphocyte proliferation and IFN-γ+ T cells production in vitro, alleviated liver injury by decreasing infiltrating inflammatory T cells producing IFN-γ in the liver and peripheral immune tissues, and demonstrated that TPN10475 weakened the activation and function of T cells by inhibiting PI3K-AKT signaling pathway. These results suggested that TPN10475 may be a potential drug for the treatment of AIH, and the inhibition of PI3K-AKT signaling pathway may provide new ideas for the study of the pathogenesis of AIH.
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Affiliation(s)
- Chun Wang
- Putuo People's Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China
| | - Mengyao Han
- Putuo People's Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China
| | - Xinhang Li
- Putuo People's Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China
| | - Jie Lv
- Putuo People's Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China
| | - Wei Zhuang
- Putuo People's Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing 100049, China; National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
| | - Ling Xie
- Putuo People's Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China
| | - Guangyu Liu
- Putuo People's Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China
| | - Kaidireya Saimaier
- Putuo People's Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China
| | - Sanxing Han
- Putuo People's Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China
| | - Changjie Shi
- Putuo People's Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China
| | - Qiuhong Hua
- Putuo People's Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China
| | - Ru Zhang
- Putuo People's Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China
| | - Xiangrui Jiang
- University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing 100049, China; CAS Key Laboratory for Receptor Research, Shanghai Institute of Materia, Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China
| | - Guiying Wang
- Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, National Stem Cell Translational Resource Center, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
| | - Changsheng Du
- Putuo People's Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
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12
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Wei X, Cheng X, Luo Y, Li X. Umbilical Cord-Derived Mesenchymal Stem Cells Attenuate S100-Induced Autoimmune Hepatitis via Modulating Th1 and Th17 Cell Responses in Mice. Stem Cells Int 2023; 2023:9992207. [PMID: 37881518 PMCID: PMC10597736 DOI: 10.1155/2023/9992207] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Revised: 09/08/2023] [Accepted: 09/19/2023] [Indexed: 10/27/2023] Open
Abstract
Currently, the first-line treatment for autoimmune hepatitis (AIH) is still the combination of glucocorticoids or immunosuppressants. However, hormone and immunosuppressive therapy can cause serious side effects, such as Cushing syndrome and bone marrow suppression. Previous studies reported on the applicability and safety of mesenchymal stem cells (MSCs) to ameliorate liver inflammation and fibrosis. However, the characteristics of MSCs sources directly contribute to the different conclusions on the mechanisms underlying MSC-mediated immunoregulation. Bone marrow-derived MSCs can exert an immunosuppression effect to ameliorate the S100-induced AIH model by inhibiting several proinflammatory cytokines and upregulating of PD-L1 in liver tissue. It is not clear whether human umbilical cord-derived MSCs (hUC-MSCs) could directly inhibit liver inflammation and ultimately alleviate the dysfunction of hepatocytes in the AIH model. First, hUC-MSCs were extracted from umbilical cord tissue, and the basic biological properties and multilineage differentiation potential were examined. Second, 1 × 106 hUC-MSCs were administered intravenously to AIH mice. At the peak of the disease, serum levels of alanine aminotransferase and aspartate aminotransferase and pathologic damage to liver tissue were measured to evaluate liver function and degree of inflammation. We also observed that the infiltration of CD4+ T cells in the liver was significantly reduced. Furthermore, the frequency of the splenic IFNγ- and IL-17A- producing CD4+ T cells were also significantly decreased, while we only observed an increasing trend in Treg cells in liver tissue. Third, an RNA sequencing analysis of liver tissue was performed, which showed that in the UC-MSC-treated group, the transcriptional profiles of inflammation-related signaling pathways were significantly negatively regulated compared to those of phosphate-buffered saline-treated mice. Collectively, these findings indicated the potential of hUC-MSC to suppress immune responses in immune anomaly mediated liver disease, thus offering a potential clinical option to improve AIH.
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Affiliation(s)
- Xiaofeng Wei
- The First Hospital of Lanzhou University, Lanzhou City, Gansu Province, China
- Key Laboratory of Biotherapy and Regenerative Medicine, The First Hospital of Lanzhou University, Lanzhou City, Gansu Province 730000, China
| | - Xinhong Cheng
- The First School of Clinical Medicine, Lanzhou University, Lanzhou City, Gansu Province, China
| | - Yang Luo
- The First Hospital of Lanzhou University, Lanzhou City, Gansu Province, China
- Key Laboratory of Biotherapy and Regenerative Medicine, The First Hospital of Lanzhou University, Lanzhou City, Gansu Province 730000, China
| | - Xun Li
- The First Hospital of Lanzhou University, Lanzhou City, Gansu Province, China
- Key Laboratory of Biotherapy and Regenerative Medicine, The First Hospital of Lanzhou University, Lanzhou City, Gansu Province 730000, China
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13
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Qin H, Sun C, Kong D, Zhu Y, Shao B, Ren S, Wang H, Zhang J, Xu Y, Wang H. CD73 mediates the therapeutic effects of endometrial regenerative cells in concanavalin A-induced hepatitis by regulating CD4 + T cells. Stem Cell Res Ther 2023; 14:277. [PMID: 37775797 PMCID: PMC10543328 DOI: 10.1186/s13287-023-03505-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Accepted: 09/20/2023] [Indexed: 10/01/2023] Open
Abstract
BACKGROUND As a kind of mesenchymal-like stromal cells, endometrial regenerative cells (ERCs) have been demonstrated effective in the treatment of Concanavalin A (Con A)-induced hepatitis. However, the therapeutic mechanism of ERCs is not fully understood. Ecto-5`-nucleotidase (CD73), an enzyme that could convert immune-stimulative adenosine monophosphate (AMP) to immune-suppressive adenosine (ADO), was identified highly expressed on ERCs. The present study was conducted to investigate whether the expression of CD73 on ERCs is critical for its therapeutic effects in Con A-induced hepatitis. METHODS ERCs knocking out CD73 were generated with lentivirus-mediated CRISPR-Cas9 technology and identified by flow cytometry, western blot and AMPase activity assay. CD73-mediated immunomodulatory effects of ERCs were investigated by CD4+ T cell co-culture assay in vitro. Besides, Con A-induced hepatitis mice were randomly assigned to the phosphate-buffered saline treated (untreated), ERC-treated, negative lentiviral control ERC (NC-ERC)-treated, and CD73-knockout-ERC (CD73-KO-ERC)-treated groups, and used to assess the CD73-mediated therapeutic efficiency of ERCs. Hepatic histopathological analysis, serum transaminase concentrations, and the proportion of CD4+ T cell subsets in the liver and spleen were performed to assess the progression degree of hepatitis. RESULTS Expression of CD73 on ERCs could effectively metabolize AMP to ADO, thereby inhibiting the activation and function of conventional CD4+ T cells was identified in vitro. In addition, ERCs could markedly reduce levels of serum and liver transaminase and attenuate liver damage, while the deletion of CD73 on ERCs dampens these effects. Furthermore, ERC-based treatment achieved less infiltration of CD4+ T and Th1 cells in the liver and reduced the population of systemic Th1 and Th17 cells and the levels of pro-inflammatory cytokines such as IFN-γ and TNF-α, while promoting the generation of Tregs in the liver and spleen, while deletion of CD73 on ERCs significantly impaired their immunomodulatory effects locally and systemically. CONCLUSION Taken together, it is concluded that CD73 is critical for the therapeutic efficiency of ERCs in the treatment of Con A-induced hepatitis.
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Affiliation(s)
- Hong Qin
- Department of General Surgery, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, China
- Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, 300052, China
| | - Chenglu Sun
- Department of General Surgery, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, China
- Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, 300052, China
| | - Dejun Kong
- School of Medicine, Nankai University, Tianjin, 300071, China
| | - Yanglin Zhu
- Department of General Surgery, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, China
- Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, 300052, China
| | - Bo Shao
- Department of General Surgery, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, China
- Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, 300052, China
| | - Shaohua Ren
- Department of General Surgery, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, China
- Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, 300052, China
| | - Hongda Wang
- Department of General Surgery, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, China
- Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, 300052, China
| | - Jingyi Zhang
- Department of General Surgery, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, China
- Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, 300052, China
| | - Yini Xu
- Department of General Surgery, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, China
- Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, 300052, China
| | - Hao Wang
- Department of General Surgery, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, China.
- Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, 300052, China.
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Yang X, Zong C, Feng C, Zhang C, Smirnov A, Sun G, Shao C, Zhang L, Hou X, Liu W, Meng Y, Zhang L, Shao C, Wei L, Melino G, Shi Y. Hippo Pathway Activation in Aged Mesenchymal Stem Cells Contributes to the Dysregulation of Hepatic Inflammation in Aged Mice. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023; 10:e2300424. [PMID: 37544916 PMCID: PMC10520691 DOI: 10.1002/advs.202300424] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Revised: 07/14/2023] [Indexed: 08/08/2023]
Abstract
Aging is always accompanied by chronic diseases which probably attribute to long-term chronic inflammation in the aging body. Whereas, the mechanism of chronic inflammation in aging body is still obscure. Mesenchymal stem cells (MSCs) are capable of local chemotaxis to sites of inflammation and play a powerful role in immune regulation. Whether degeneration of MSCs in the aging body is associated with unbalanced inflammation is still not clear. In this study, immunosuppressive properties of aged MSCs are found to be repressed. The impaired immunosuppressive function of aged MSCs is associated with lower expression of the Hippo effector Yes-associated protein 1 (YAP1) and its target gene signal transducer and activator of transcription 1 (STAT1). YAP1 regulates the transcription of STAT1 through binding with its promoter. In conclusion, a novel YAP1/STAT1 axis maintaining immunosuppressive function of MSCs is revealed and impairment of this signal pathway in aged MSCs probably resulted in higher inflammation in aged mice liver.
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Affiliation(s)
- Xue Yang
- The Third Affiliated Hospital of Soochow UniversityInstitutes for Translational MedicineState Key Laboratory of Radiation Medicine and ProtectionKey Laboratory of Stem Cells and Medical Biomaterials of Jiangsu ProvinceMedical College of Soochow UniversitySoochow UniversitySuzhou215000China
- Department of Experimental MedicineTORUniversity of Rome Tor VergataRome00133Italy
- Department of Tumor Immunology and Gene Therapy CenterThird Affiliated Hospital of Naval Medical UniversityShanghai200438China
- Department of immunology and metabolismNational Center for Liver CancerShanghai201805China
| | - Chen Zong
- Department of Tumor Immunology and Gene Therapy CenterThird Affiliated Hospital of Naval Medical UniversityShanghai200438China
- Department of immunology and metabolismNational Center for Liver CancerShanghai201805China
| | - Chao Feng
- The Third Affiliated Hospital of Soochow UniversityInstitutes for Translational MedicineState Key Laboratory of Radiation Medicine and ProtectionKey Laboratory of Stem Cells and Medical Biomaterials of Jiangsu ProvinceMedical College of Soochow UniversitySoochow UniversitySuzhou215000China
- Department of Experimental MedicineTORUniversity of Rome Tor VergataRome00133Italy
| | - Cangang Zhang
- Department of Pathogenic Microbiology and ImmunologySchool of Basic Medical SciencesXi'an Jiaotong UniversityXi'anShaanxi710061China
| | - Artem Smirnov
- Department of Experimental MedicineTORUniversity of Rome Tor VergataRome00133Italy
| | - Gangqi Sun
- Department of Clinical PharmacologyThe Second Hospital of Anhui Medical UniversityHefei230601China
| | - Changchun Shao
- Department of OncologyThe First Affiliated Hospital of Anhui Medical UniversityHefeiAnhui230022China
| | - Luyao Zhang
- Department of Clinical PharmacologyThe Second Hospital of Anhui Medical UniversityHefei230601China
| | - Xiaojuan Hou
- Department of Tumor Immunology and Gene Therapy CenterThird Affiliated Hospital of Naval Medical UniversityShanghai200438China
- Department of immunology and metabolismNational Center for Liver CancerShanghai201805China
| | - Wenting Liu
- Department of Tumor Immunology and Gene Therapy CenterThird Affiliated Hospital of Naval Medical UniversityShanghai200438China
- Department of immunology and metabolismNational Center for Liver CancerShanghai201805China
| | - Yan Meng
- Department of Tumor Immunology and Gene Therapy CenterThird Affiliated Hospital of Naval Medical UniversityShanghai200438China
- Department of immunology and metabolismNational Center for Liver CancerShanghai201805China
| | - Liying Zhang
- The Third Affiliated Hospital of Soochow UniversityInstitutes for Translational MedicineState Key Laboratory of Radiation Medicine and ProtectionKey Laboratory of Stem Cells and Medical Biomaterials of Jiangsu ProvinceMedical College of Soochow UniversitySoochow UniversitySuzhou215000China
| | - Changshun Shao
- The Third Affiliated Hospital of Soochow UniversityInstitutes for Translational MedicineState Key Laboratory of Radiation Medicine and ProtectionKey Laboratory of Stem Cells and Medical Biomaterials of Jiangsu ProvinceMedical College of Soochow UniversitySoochow UniversitySuzhou215000China
| | - Lixin Wei
- Department of Tumor Immunology and Gene Therapy CenterThird Affiliated Hospital of Naval Medical UniversityShanghai200438China
- Department of immunology and metabolismNational Center for Liver CancerShanghai201805China
| | - Gerry Melino
- Department of Experimental MedicineTORUniversity of Rome Tor VergataRome00133Italy
| | - Yufang Shi
- The Third Affiliated Hospital of Soochow UniversityInstitutes for Translational MedicineState Key Laboratory of Radiation Medicine and ProtectionKey Laboratory of Stem Cells and Medical Biomaterials of Jiangsu ProvinceMedical College of Soochow UniversitySoochow UniversitySuzhou215000China
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15
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Zhu J, Chen H, Cui J, Zhang X, Liu G. Oroxylin A inhibited autoimmune hepatitis-induced liver injury and shifted Treg/Th17 balance to Treg differentiation. Exp Anim 2023; 72:367-378. [PMID: 36927981 PMCID: PMC10435359 DOI: 10.1538/expanim.22-0171] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Accepted: 03/06/2023] [Indexed: 03/16/2023] Open
Abstract
Autoimmune hepatitis (AIH) is a kind of autoimmune disease mediated by T cells, and its incidence is gradually increasing in the world. Oroxylin A (OA) is one of the major bioactive flavonoids that has been reported to inhibit inflammatory. Here, an AIH model of mouse was induced by Concanavalin A (Con A). It found that serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were decreased in mice with the treatment of OA. Hematoxylin-eosin staining showed that the liver injury was attenuated by OA, and TUNEL staining indicated that the cells apoptosis of liver was weakened in mice with OA treatment. ELISA analysis of cytokines and chemokines suggested that OA reduced the expression of IL-6, IL-17A, chemokine ligand 2 (CCL2), C-X-C motif chemokine ligand 1 (CXCL1) and CXCL10, but promoted the expression of IL-10 and TGF-β in mice. The mRNA levels of Il-17a in liver and spleen tissues were also significantly decreased, on the contrary, the mRNA levels of Il-10 in liver and spleen tissues were increased. The proportion of Treg/Th17 detected by flow cytometry revealed that OA promoted the differentiation of Treg and inhibited the differentiation of Th17 both in the liver and spleen. The results of this study demonstrated the inhibitory effects of OA on AIH-induced liver injury and the inflammatory response of AIH, and revealed that OA affected the balance of Treg/Th17 and shifted the balance toward Treg differentiation. It provided new potential drugs for the prevention of AIH.
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Affiliation(s)
- Jinxia Zhu
- The First Clinical Medical College, Henan University of Chinese Medicine, 156 Jinshui East Road, Zhengzhou, Henan, 450046, P.R. China
| | - Hongxiu Chen
- The First Clinical Medical College, Henan University of Chinese Medicine, 156 Jinshui East Road, Zhengzhou, Henan, 450046, P.R. China
| | - Jianjiao Cui
- Spleen, Stomach and Hepatobiliary Department, The First Affiliated Hospital of Henan University of Chinese Medicine, No. 19, Renmin Road, Zhengzhou, Henan, 450003, P.R. China
| | - Xiaorui Zhang
- Spleen, Stomach and Hepatobiliary Department, The First Affiliated Hospital of Henan University of Chinese Medicine, No. 19, Renmin Road, Zhengzhou, Henan, 450003, P.R. China
| | - Guangwei Liu
- Spleen, Stomach and Hepatobiliary Department, The First Affiliated Hospital of Henan University of Chinese Medicine, No. 19, Renmin Road, Zhengzhou, Henan, 450003, P.R. China
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16
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Rani R, Gandhi CR. Stellate cell in hepatic inflammation and acute injury. J Cell Physiol 2023; 238:1226-1236. [PMID: 37120832 DOI: 10.1002/jcp.31029] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 04/05/2023] [Accepted: 04/07/2023] [Indexed: 05/02/2023]
Abstract
The perisinusoidal hepatic stellate cells (HSCs) have been investigated extensively for their role as the major fibrogenic cells during chronic liver injury. HSCs also produce numerous cytokines, chemokines, and growth mediators, and express cell adhesion molecules constitutively and in response to stimulants such as endotoxin (lipopolysaccharide). With this property and by interacting with resident and recruited immune and inflammatory cells, HSCs regulate hepatic immune homeostasis, inflammation, and acute injury. Indeed, experiments with HSC-depleted animal models and cocultures have provided evidence for the prominent role of HSCs in the initiation and progression of inflammation and acute liver damage due to various toxic agents. Thus HSCs and/or mediators derived thereof during acute liver damage may be considered as potential therapeutic targets.
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Affiliation(s)
- Richa Rani
- Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
- Research & Development, Cincinnati Veterans Administration Medical Center, Cincinnati, Ohio, USA
| | - Chandrashekhar R Gandhi
- Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
- Research & Development, Cincinnati Veterans Administration Medical Center, Cincinnati, Ohio, USA
- Department of Surgery, University of Cincinnati, Cincinnati, Ohio, USA
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17
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Zhao J, Jeong H, Yang D, Tian W, Kim JW, Woong Lim C, Kim B. Toll-like receptor-7 signaling in Kupffer cells exacerbates concanavalin A-induced liver injury in mice. Int Immunopharmacol 2023; 119:110238. [PMID: 37126986 DOI: 10.1016/j.intimp.2023.110238] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Revised: 04/19/2023] [Accepted: 04/21/2023] [Indexed: 05/03/2023]
Abstract
Concanavalin A (ConA) is a plant lectin that can induce immune-mediated liver damage. ConA induced liver damage animal model is a widely accepted model that can mimic clinical acute hepatitis and immune-mediated liver injury in humans. Toll-like receptor-7 (TLR7), a member of the TLR family, plays a key role in pathogen recognition and innate immune activation. The aim of this study was to examine the role of TLR7 in the pathogenesis of ConA-induced liver injury. Acute liver injury was induced by intravenous injection with ConA in WT (wild-type) and TLR7 knockout (KO) mice. Results showed that attenuated liver injury in TLR7-deficient mice, as indicated by increased survival rate, decreased aminotransferase levels, and reduced pathological lesions, was associated with decreased release of pro-inflammatory cytokines in livers. Consistently, significantly decreased proliferation of CD4+ T cell was detected in ConA-stimulated TLR7-deficient splenocytes, but not in CD3/CD28 stimulated TLR7-deficient CD4+ T cells. Moreover, TLR7 deficiency in KCs specifically suppressed the expression of TNF-α (tumor necrosis factor-α). Depletion of KCs abolished the detrimental role of TLR7 in ConA-induced liver injury. Taken together, these results demonstrate that TLR7 can regulate the expression of TNF-α in KCs, which is necessary for the full progression of ConA-induced liver injury.
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Affiliation(s)
- Jing Zhao
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang, Henan, People's Republic of China; Biosafety Research Institute and College of Veterinary Medicine, Jeonbuk National University, Iksan, Jeonbuk, Republic of Korea.
| | - Hyuneui Jeong
- Biosafety Research Institute and College of Veterinary Medicine, Jeonbuk National University, Iksan, Jeonbuk, Republic of Korea.
| | - Daram Yang
- Biosafety Research Institute and College of Veterinary Medicine, Jeonbuk National University, Iksan, Jeonbuk, Republic of Korea.
| | - Weishun Tian
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang, Henan, People's Republic of China.
| | - Jong-Won Kim
- Biosafety Research Institute and College of Veterinary Medicine, Jeonbuk National University, Iksan, Jeonbuk, Republic of Korea.
| | - Chae Woong Lim
- Biosafety Research Institute and College of Veterinary Medicine, Jeonbuk National University, Iksan, Jeonbuk, Republic of Korea.
| | - Bumseok Kim
- Biosafety Research Institute and College of Veterinary Medicine, Jeonbuk National University, Iksan, Jeonbuk, Republic of Korea.
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18
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Liu G, Zhang Y, Han S, Zhuang W, Lv J, Han M, Xie L, Jiang X, Wang C, Saimaier K, Shen J, Du C. TPN10466 ameliorates Concanavalin A-induced autoimmune hepatitis in mice via inhibiting ERK/JNK/p38 signaling pathway. Eur J Immunol 2023; 53:e2250100. [PMID: 36648433 DOI: 10.1002/eji.202250100] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Revised: 11/30/2022] [Accepted: 01/16/2023] [Indexed: 01/18/2023]
Abstract
Autoimmune hepatitis (AIH) eventually progresses to liver fibrosis, cirrhosis, and even hepatocellular carcinoma, causing irreversible damage to the liver. Concanavalin A-induced hepatitis in mice is a well-established model with pathophysiology similar to that of immune-mediated liver injury in human viral and autoimmune hepatitis, and it has been widely used to explore the pathogenesis and clinical treatment of human immune hepatitis. Artemisinin has been shown to exhibit anti-inflammatory effects through unclear mechanisms. In this study, we aimed to assess the effect of the artemisinin derivative TPN10466 on AIH. In vitro studies showed that TPN10466 dose dependently inhibited the percentage of IFN-γ-producing T cells. Further studies showed that TPN10466 attenuated the disease severity of AIH by downregulating the ability of lymphocytes to secrete IFN-γ and by reducing lymphocyte number in the liver. In addition, we found that TPN10466 treatment reduced T-cell responses by inhibiting JNK, ERK, and p38 pathways. In conclusion, our work suggests that TPN10466 provides protection against the autoimmune disease AIH by suppressing the inflammatory response of T cells, suggesting that TPN10466 may be a promising potential agent for the treatment of AIH.
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Affiliation(s)
- Guangyu Liu
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopaedic Department of Tongji Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Yan Zhang
- University of Chinese Academy of Sciences, Beijing, China
- Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Urumqi, China
| | - Sansheng Han
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopaedic Department of Tongji Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Wei Zhuang
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopaedic Department of Tongji Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China
- University of Chinese Academy of Sciences, Beijing, China
- Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
| | - Jie Lv
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopaedic Department of Tongji Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Mengyao Han
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopaedic Department of Tongji Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Ling Xie
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopaedic Department of Tongji Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Xiangrui Jiang
- University of Chinese Academy of Sciences, Beijing, China
- CAS Key Laboratory for Receptor Research, Shanghai Institute of Materia, Medica, Chinese Academy of Sciences, Shanghai, China
| | - Chun Wang
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopaedic Department of Tongji Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Kaidireya Saimaier
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopaedic Department of Tongji Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Jingshan Shen
- University of Chinese Academy of Sciences, Beijing, China
- CAS Key Laboratory for Receptor Research, Shanghai Institute of Materia, Medica, Chinese Academy of Sciences, Shanghai, China
| | - Changsheng Du
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopaedic Department of Tongji Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China
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19
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Low-Dose Colchicine Attenuates Sepsis-Induced Liver Injury: A Novel Method for Alleviating Systemic Inflammation. Inflammation 2023; 46:963-974. [PMID: 36656466 DOI: 10.1007/s10753-023-01783-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 01/06/2023] [Accepted: 01/09/2023] [Indexed: 01/20/2023]
Abstract
Sepsis is a significant public health challenge. The immune system underlies the pathogenesis of the disease. The liver is both an active player and a target organ in sepsis. Targeting the gut immune system using low-dose colchicine is an attractive method for alleviating systemic inflammation in sepsis without inducing immunosuppression. The present study aimed to determine the use of low-dose colchicine in LPS-induced sepsis in mice. C67B mice were injected intraperitoneal with LPS to induce sepsis. The treatment group received 0.02 mg/kg colchicine daily by gavage. Short and extended models were performed, lasting 3 and 5 days, respectively. We followed the mice for biochemical markers of end-organ injury, blood counts, cytokine levels, and liver pathology and conducted proteomic studies on liver samples. Targeting the gut immune system using low-dose colchicine improved mice's well-being measured by the murine sepsis score. Treatment alleviated the liver injury in septic mice, manifested by a significant decrease in their liver enzyme levels, including ALT, AST, and LDH. Treatment exerted a trend to reduce creatinine levels. Low-dose colchicine improved liver pathology, reduced inflammation, and reduced the pro-inflammatory cytokine TNFα and IL1-β levels. A liver proteomic analysis revealed low-dose colchicine down-regulated sepsis-related proteins, alpha-1 antitrypsin, and serine dehydratase. Targeting the gut immune system using low-dose colchicine attenuated liver injury in LPS-induced sepsis, reducing the pro-inflammatory cytokine levels. Low-dose colchicine provides a safe method for immunomodulation for multiple inflammatory disorders.
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20
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Multi-Omics Analysis Reveals the Protection of Gasdermin D in Concanavalin A-Induced Autoimmune Hepatitis. Microbiol Spectr 2022; 10:e0171722. [PMID: 35972273 PMCID: PMC9602755 DOI: 10.1128/spectrum.01717-22] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Autoimmune hepatitis (AIH) is a progressive inflammation-associated liver injury. Pyroptosis is a novel inflammatory programmed cell death wherein gasdermin D (GSDMD) serves as the executioner. Our work challenged Gsdmd-/- mice with concanavalin A (ConA) to try to unveil the actual role of GSDMD in AIH. After ConA injection, Gsdmd-/- mice exhibited more severe liver damage characterized by a lower survival rate, more extensive hepatocyte necrosis and apoptosis, and higher serum transaminase levels, indicating the protection of GSDMD in ConA-induced AIH. Furthermore, the Gsdmd-/- mice exhibited higher hepatic expression and serum levels of inflammatory cytokines (gamma interferon [IFN-γ], tumor necrosis factor alpha [TNF-α], and interleukin-17A [IL-17A]) and more infiltration of macrophages and neutrophils after ConA treatment than did wild-type (WT) mice. Gsdmd-/- mice with AIH showed increased hepatic l-glutamine levels but decreased glycerophospholipid metabolites levels. L-glutamine levels showed positive correlations while glycerophospholipid metabolites showed negative associations with liver injury indexes and inflammation markers. We further observed a destroyed intestinal barrier in Gsdmd-/- mice after ConA injection as indicated by decreased transcriptional expressions of Tjp1, Ocln, Reg3g, and Muc2. ConA-treated Gsdmd-/- mice also exhibited higher serum LPS binding protein (LBP) concentrations and hepatic Tlr4 and Cd14 mRNA levels. Further fecal 16S rRNA gene sequencing demonstrated decreased relative abundances of Lactobacillus and Roseburia but increased relative abundances of Allobaculum and Dubosiella in Gsdmd-/- mice with AIH. Lactobacillus was negatively correlated with liver injury and inflammation indexes and positively associated with Ocln, Muc2, and Reg3g levels. Allobaculum was positively related to liver injury and inflammatory cytokines and negatively correlated with gut barrier indexes. IMPORTANCE Our study provides the first direct clues to the protective role of gasdermin D (GSDMD) in autoimmune hepatitis (AIH). We demonstrated that Gsdmd knockout exacerbated concanavalin A (ConA)-induced AIH in mice. It may be due to the destroyed intestinal barrier and changes in certain intestinal microbes and hepatic metabolites resulting in increased liver injury and inflammation in ConA-treated Gsdmd-/- mice. This finding suggested a nonnegligible role of GSDMD in AIH and also confirmed its physiological nonpyroptosis effects on the host. The role of GSDMD in autoimmune liver diseases or other liver diseases is complex and intriguing, deserving deep investigation.
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21
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Shao F, Ci L, Shi J, Fang F, Yan B, Liu X, Yao X, Zhang M, Yang H, Wang Z, Fei J. Bioluminescence imaging of mouse monocyte chemoattractant protein-1 expression in inflammatory processes. Acta Biochim Biophys Sin (Shanghai) 2022; 54:1507-1517. [PMID: 36239355 PMCID: PMC9828394 DOI: 10.3724/abbs.2022143] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Monocyte chemoattractant protein-1 (MCP-1) plays a crucial role in various inflammatory diseases. To reveal the impact of MCP-1 during diseases and to develop anti-inflammatory agents, we establish a transgenic mouse line. The firefly luciferase gene is incorporated into the mouse genome and driven by the endogenous MCP-1 promoter. A bioluminescence photographing system is applied to monitor luciferase levels in live mice during inflammation, including lipopolysaccharide-induced sepsis, concanavalin A-induced T cell-dependent liver injury, CCl 4-induced acute hepatitis, and liver fibrosis. The results demonstrate that the luciferase signal induced in inflammatory processes is correlated with endogenous MCP-1 expression in mice. Furthermore, the expressions of MCP-1 and the luciferase gene are dramatically inhibited by administration of the anti-inflammatory drug dexamethasone in a septicemia model. Our results suggest that the transgenic MCP-1-Luc mouse is a useful model to study MCP-1 expression in inflammation and disease and to evaluate the efficiency of anti-inflammatory drugs in vivo.
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Affiliation(s)
- Fangyang Shao
- School of Life Sciences and TechnologyTongji UniversityShanghai200092China,Institute of BiophysicsChinese Academy of SciencesBeijing100101China,College of Life SciencesUniversity of Chinese Academy of SciencesBeijing100049China
| | - Lei Ci
- Shanghai Engineering Research Center for Model OrganismsSMOCShanghai201203China,Correspondence address. Tel: +86-21-65982429; (J.F.) / Tel: +86-21-20791155; (L.C.) @modelorg.com
| | - Jiahao Shi
- School of Life Sciences and TechnologyTongji UniversityShanghai200092China
| | - Fei Fang
- School of Life Sciences and TechnologyTongji UniversityShanghai200092China
| | - Bowen Yan
- School of Life Sciences and TechnologyTongji UniversityShanghai200092China
| | - Xijun Liu
- School of Life Sciences and TechnologyTongji UniversityShanghai200092China
| | - Xiangyu Yao
- School of Life Sciences and TechnologyTongji UniversityShanghai200092China
| | - Mengjie Zhang
- School of Life Sciences and TechnologyTongji UniversityShanghai200092China
| | - Hua Yang
- School of Life Sciences and TechnologyTongji UniversityShanghai200092China
| | - Zhugang Wang
- Shanghai Engineering Research Center for Model OrganismsSMOCShanghai201203China
| | - Jian Fei
- School of Life Sciences and TechnologyTongji UniversityShanghai200092China,Correspondence address. Tel: +86-21-65982429; (J.F.) / Tel: +86-21-20791155; (L.C.) @modelorg.com
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22
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Kathem SH, Abdulsahib WK, Zalzala MH. Berbamine and thymoquinone exert protective effects against immune-mediated liver injury via NF-κB dependent pathway. Front Vet Sci 2022; 9:960981. [PMID: 35958317 PMCID: PMC9360574 DOI: 10.3389/fvets.2022.960981] [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: 06/03/2022] [Accepted: 07/07/2022] [Indexed: 11/13/2022] Open
Abstract
Background Immune-mediated hepatitis is a severe impendence to human health, and no effective treatment is currently available. Therefore, new, safe, low-cost therapies are desperately required. Berbamine (BE), a natural substance obtained primarily from Berberis vulgaris L, is a traditional herbal medicine with several bioactivities, such as antimicrobial and anticancer activities. Thymoquinone (TQ), a phytochemical molecule derived from the Nigella sativa plant's black cumin seeds, has attracted interest owing to itsanti-inflammatory, antioxidant, and anticancer properties. Aim This current study's aims was to examine the protective impacts of BE and TQ in Concanavalin A (ConA)- induced acute liver injury and the action's underlying mechanism. Methods sixty mice of both sexes were used and divided into four groups (each group with six mice) as follows: Group I obtained distilled water (negative control group). Group II received distilled water with a single dose of 0.1 ml ConA (20 mg/kg) on day 4 by retro-orbital route (model group). Groups III and IV received BE (30 mg/kg/day) and TQ (25 mg/kg/day), respectively, by oral gavage for four successive days, with a single dose of ConA (20 mg/kg) on day 4, then all animals were sacrificed after 8 h and prepared for liver and blood collection. Results ConA administration increased the ALT, AST, TNF-α, INFγ, and NF-κB significantly (p < 0.001) in the model group. Both BE and TQ could reduce these parameters significantly (p < 0.001) in groups III and IV, respectively, compared to the model group. Conclusion Both BE and TQ prominently attenuated ConA immune-mediated liver injury. These findings give a remarkable insight into developing a new therapeutic agent for treating hepatitis and other autoimmune diseases.
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Affiliation(s)
- Sarmed H. Kathem
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Baghdad, Baghdad, Iraq
| | - Waleed K. Abdulsahib
- Department of Pharmacology and Toxicology, College of Pharmacy, Al Farahidi University, Baghdad, Iraq
- *Correspondence: Waleed K. Abdulsahib
| | - Munaf H. Zalzala
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Baghdad, Baghdad, Iraq
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23
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Pandey SP, Bender MJ, McPherson AC, Phelps CM, Sanchez LM, Rana M, Hedden L, Sangani KA, Chen L, Shapira JH, Siller M, Goel C, Verdú EF, Jabri B, Chang A, Chandran UR, Mullett SJ, Wendell SG, Singhi AD, Tilstra JS, Pierre JF, Arteel GE, Hinterleitner R, Meisel M. Tet2 deficiency drives liver microbiome dysbiosis triggering Tc1 cell autoimmune hepatitis. Cell Host Microbe 2022; 30:1003-1019.e10. [PMID: 35658976 PMCID: PMC9841318 DOI: 10.1016/j.chom.2022.05.006] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Revised: 03/04/2022] [Accepted: 05/09/2022] [Indexed: 01/19/2023]
Abstract
The triggers that drive interferon-γ (IFNγ)-producing CD8 T cell (Tc1 cell)-mediated autoimmune hepatitis (AIH) remain obscure. Here, we show that lack of hematopoietic Tet methylcytosine dioxygenase 2 (Tet2), an epigenetic regulator associated with autoimmunity, results in the development of microbiota-dependent AIH-like pathology, accompanied by hepatic enrichment of aryl hydrocarbon receptor (AhR) ligand-producing pathobionts and rampant Tc1 cell immunity. We report that AIH-like disease development is dependent on both IFNγ and AhR signaling, as blocking either reverts ongoing AIH-like pathology. Illustrating the critical role of AhR-ligand-producing pathobionts in this condition, hepatic translocation of the AhR ligand indole-3-aldehyde (I3A)-releasing Lactobacillus reuteri is sufficient to trigger AIH-like pathology. Finally, we demonstrate that I3A is required for L. reuteri-induced Tc1 cell differentiation in vitro and AIH-like pathology in vivo, both of which are restrained by Tet2 within CD8 T cells. This AIH-disease model may contribute to the development of therapeutics to alleviate AIH.
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Affiliation(s)
- Surya P Pandey
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Mackenzie J Bender
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Alex C McPherson
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Infectious Diseases and Microbiology, University of Pittsburgh School of Public Health, Pittsburgh, PA, USA
| | - Catherine M Phelps
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | | | - Mohit Rana
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Lee Hedden
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Kishan A Sangani
- Department of Medicine, University of Chicago, Chicago, IL, USA; Committee on Immunology, University of Chicago, Chicago, IL, USA
| | - Li Chen
- Department of Medicine, University of Chicago, Chicago, IL, USA; Committee on Immunology, University of Chicago, Chicago, IL, USA
| | - Jake H Shapira
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Magdalena Siller
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Chhavi Goel
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Elena F Verdú
- Division of Gastroenterology, Department of Internal Medicine, Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada
| | - Bana Jabri
- Department of Medicine, University of Chicago, Chicago, IL, USA; Committee on Immunology, University of Chicago, Chicago, IL, USA; Department of Pathology, University of Chicago, Chicago, IL, USA; Department of Pediatrics, University of Chicago, Chicago, IL, USA
| | - Alexander Chang
- Department of Biomedical Informatics, University of Pittsburgh, Pittsburgh, PA, USA
| | - Uma R Chandran
- Department of Biomedical Informatics, University of Pittsburgh, Pittsburgh, PA, USA
| | - Steven J Mullett
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Health Sciences Metabolomics and Lipidomics Core, University of Pittsburgh, Pittsburgh, PA, USA
| | - Stacy G Wendell
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Health Sciences Metabolomics and Lipidomics Core, University of Pittsburgh, Pittsburgh, PA, USA
| | - Aatur D Singhi
- Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Jeremy S Tilstra
- Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Joseph F Pierre
- Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, WI, USA
| | - Gavin E Arteel
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA, USA
| | - Reinhard Hinterleitner
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Marlies Meisel
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
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24
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Diamond T, Burn TN, Nishiguchi MA, Minichino D, Chase J, Chu N, Kreiger PA, Behrens EM. Familial hemophagocytic lymphohistiocytosis hepatitis is mediated by IFN-γ in a predominantly hepatic-intrinsic manner. PLoS One 2022; 17:e0269553. [PMID: 35671274 PMCID: PMC9173616 DOI: 10.1371/journal.pone.0269553] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2022] [Accepted: 05/23/2022] [Indexed: 12/03/2022] Open
Abstract
Interferon gamma (IFN-γ) is the main cytokine driving organ dysfunction in Familial Hemophagocytic Lymphohistiocytosis (FHL). Blockade of IFN-γ pathway ameliorates FHL hepatitis, both in animal models and in humans with FHL. Hepatocytes are known to express IFN-γ receptor (IFN-γ-R). However, whether IFN-γ induced hepatitis in FHL is a lymphocyte or liver intrinsic response to the cytokine has yet to be elucidated. Using a IFNgR-/- bone marrow chimeric model, this study showed that non-hematopoietic IFN-γ response is critical for development of FHL hepatitis in LCMV-infected Prf1-/- mice. Lack of hepatic IFN-γ responsiveness results in reduced hepatitis as measured by hepatomegaly, alanine aminotransferase (ALT) levels and abrogated histologic endothelial inflammation. In addition, IFN-γ non-hematopoietic response was critical in activation of lymphocytes by soluble interleukin 2 receptor (sIL-2r) and recruitment of CD8+ effector T lymphocytes (CD8+ CD44hi CD62Llo) (Teff) and inflammatory monocytes. Lastly, non-hematopoietic IFN-γ response results in increased hepatic transcription of type 1 immune response and oxidative stress response pathways, while decreasing transcription of genes involved in extracellular matrix (ECM) production. In summary, these findings demonstrate that there is a hepatic transcriptional response to IFN-γ, likely critical in the pathogenesis of FHL hepatitis and hepatic specific responses could be a therapeutic target in this disorder.
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Affiliation(s)
- Tamir Diamond
- Division of Gastroenterology Hepatology and Nutrition, Children’s Hospital of Philadelphia, Philadelphia, PA, United States of America
| | - Thomas N. Burn
- Perlman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States of America
| | - Mailyn A. Nishiguchi
- Perlman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States of America
| | - Danielle Minichino
- Perlman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States of America
| | - Julie Chase
- Division of Rheumatology, Children’s Hospital of Philadelphia, Philadelphia, PA, United States of America
| | - Niansheng Chu
- Division of Rheumatology, Children’s Hospital of Philadelphia, Philadelphia, PA, United States of America
| | - Portia A. Kreiger
- Department of Pathology, Children’s Hospital of Philadelphia, Philadelphia, PA, United States of America
| | - Edward M. Behrens
- Division of Rheumatology, Children’s Hospital of Philadelphia, Philadelphia, PA, United States of America
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25
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Methyl butyrate attenuates concanavalin A-induced autoimmune hepatitis by inhibiting Th1-cell activation and homing to the liver. Cell Immunol 2022; 378:104575. [DOI: 10.1016/j.cellimm.2022.104575] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Revised: 06/13/2022] [Accepted: 06/21/2022] [Indexed: 11/23/2022]
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26
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Du Y, Zhang W, Qiu H, Xiao C, Shi J, Reid LM, He Z. Mouse Models of Liver Parenchyma Injuries and Regeneration. Front Cell Dev Biol 2022; 10:903740. [PMID: 35721478 PMCID: PMC9198899 DOI: 10.3389/fcell.2022.903740] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Accepted: 04/11/2022] [Indexed: 12/11/2022] Open
Abstract
Mice have genetic and physiological similarities with humans and a well-characterized genetic background that is easy to manipulate. Murine models have become the most favored, robust mammalian systems for experimental analyses of biological processes and disease conditions due to their low cost, rapid reproduction, a wealth of mouse strains with defined genetic conditions (both native ones as well as ones established experimentally), and high reproducibility with respect to that which can be done in experimental studies. In this review, we focus on murine models for liver, an organ with renown regenerative capacity and the organ most central to systemic, complex metabolic and physiological functions for mammalian hosts. Establishment of murine models has been achieved for all aspects of studies of normal liver, liver diseases, liver injuries, and regenerative repair mechanisms. We summarize key information on current mouse systems that partially model facets of clinical scenarios, particularly those associated with drug-induced acute or chronic liver injuries, dietary related, non-alcoholic liver disease (NAFLD), hepatitis virus infectious chronic liver diseases, and autoimmune hepatitis (AIH). In addition, we also include mouse models that are suitable for studying liver cancers (e.g., hepatocellular carcinomas), the aging process (senescence, apoptosis), and various types of liver injuries and regenerative processes associated with them.
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Affiliation(s)
- Yuan Du
- Department of General Surgery, Ji’an Hospital, Shanghai East Hospital, School of Medicine, Tongji University, Ji’an, China
- Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China
- The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Wencheng Zhang
- Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China
- Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, China
- Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai, China
| | - Hua Qiu
- Department of General Surgery, Ji’an Hospital, Shanghai East Hospital, School of Medicine, Tongji University, Ji’an, China
- Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China
- The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Canjun Xiao
- Department of General Surgery, Ji’an Hospital, Shanghai East Hospital, School of Medicine, Tongji University, Ji’an, China
| | - Jun Shi
- Department of General Surgery, Ji’an Hospital, Shanghai East Hospital, School of Medicine, Tongji University, Ji’an, China
- The First Affiliated Hospital of Nanchang University, Nanchang, China
- *Correspondence: Zhiying He, ; Lola M. Reid, , ; Jun Shi,
| | - Lola M. Reid
- Departments of Cell Biology and Physiology, Program in Molecular Biology and Biotechnology, UNC School of Medicine, Chapel Hill, NC, United States
- *Correspondence: Zhiying He, ; Lola M. Reid, , ; Jun Shi,
| | - Zhiying He
- Department of General Surgery, Ji’an Hospital, Shanghai East Hospital, School of Medicine, Tongji University, Ji’an, China
- Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China
- Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, China
- Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai, China
- *Correspondence: Zhiying He, ; Lola M. Reid, , ; Jun Shi,
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Chen CL, Tseng PC, Satria RD, Nguyen TT, Tsai CC, Lin CF. Role of Glycogen Synthase Kinase-3 in Interferon-γ-Mediated Immune Hepatitis. Int J Mol Sci 2022; 23:ijms23094669. [PMID: 35563060 PMCID: PMC9101719 DOI: 10.3390/ijms23094669] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Revised: 04/16/2022] [Accepted: 04/20/2022] [Indexed: 12/04/2022] Open
Abstract
Glycogen synthase kinase-3 (GSK-3), a serine/threonine kinase, is a vital glycogen synthase regulator controlling glycogen synthesis, glucose metabolism, and insulin signaling. GSK-3 is widely expressed in different types of cells, and its abundant roles in cellular bioregulation have been speculated. Abnormal GSK-3 activation and inactivation may affect its original bioactivity. Moreover, active and inactive GSK-3 can regulate several cytosolic factors and modulate their diverse cellular functional roles. Studies in experimental liver disease models have illustrated the possible pathological role of GSK-3 in facilitating acute hepatic injury. Pharmacologically targeting GSK-3 is therefore suggested as a therapeutic strategy for liver protection. Furthermore, while the signaling transduction of GSK-3 facilitates proinflammatory interferon (IFN)-γ in vitro and in vivo, the blockade of GSK-3 can be protective, as shown by an IFN-γ-induced immune hepatitis model. In this study, we explored the possible regulation of GSK-3 and the potential relevance of GSK-3 blockade in IFN-γ-mediated immune hepatitis.
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Affiliation(s)
- Chia-Ling Chen
- School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei 110, Taiwan;
| | - Po-Chun Tseng
- Core Laboratory of Immune Monitoring, Office of Research & Development, Taipei Medical University, Taipei 110, Taiwan;
| | - Rahmat Dani Satria
- International Ph.D. Program in Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan; (R.D.S.); (T.T.N.)
- Department of Clinical Pathology and Laboratory Medicine, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta 55281, Indonesia
- Clinical Laboratory Installation, Dr. Sardjito Central General Hospital, Yogyakarta 55281, Indonesia
- Department of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
| | - Thi Thuy Nguyen
- International Ph.D. Program in Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan; (R.D.S.); (T.T.N.)
- Department of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
- Department of Oncology, Hue University of Medicine and Pharmacy, Hue University, Hue City 530000, Vietnam
| | - Cheng-Chieh Tsai
- Department of Nursing, Chung Hwa University of Medical Technology, Tainan 703, Taiwan
- Department of Long Term Care Management, Chung Hwa University of Medical Technology, Tainan 703, Taiwan
- Correspondence: (C.-C.T.); (C.-F.L.)
| | - Chiou-Feng Lin
- Core Laboratory of Immune Monitoring, Office of Research & Development, Taipei Medical University, Taipei 110, Taiwan;
- International Ph.D. Program in Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan; (R.D.S.); (T.T.N.)
- Department of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
- Correspondence: (C.-C.T.); (C.-F.L.)
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Wang H, Wang Q, Yang C, Guo M, Cui X, Jing Z, Liu Y, Qiao W, Qi H, Zhang H, Zhang X, Zhao N, Zhang M, Chen M, Zhang S, Xu H, Zhao L, Qiao M, Wu Z. Bacteroides acidifaciens in the gut plays a protective role against CD95-mediated liver injury. Gut Microbes 2022; 14:2027853. [PMID: 35129072 PMCID: PMC8820816 DOI: 10.1080/19490976.2022.2027853] [Citation(s) in RCA: 48] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
The intestinal flora plays an important role in the development of many human and animal diseases. Microbiome association studies revealed the potential regulatory function of intestinal bacteria in many liver diseases, such as autoimmune hepatitis, viral hepatitis and alcoholic hepatitis. However, the key intestinal bacterial strains that affect pathological liver injury and the underlying functional mechanisms remain unclear. We found that the gut microbiota from gentamycin (Gen)-treated mice significantly alleviated concanavalin A (ConA)-induced liver injury compared to vancomycin (Van)-treated mice by inhibiting CD95 expression on the surface of hepatocytes and reducing CD95/CD95L-mediated hepatocyte apoptosis. Through the combination of microbiota sequencing and correlation analysis, we isolated 5 strains with the highest relative abundance, Bacteroides acidifaciens (BA), Parabacteroides distasonis (PD), Bacteroides thetaiotaomicron (BT), Bacteroides dorei (BD) and Bacteroides uniformis (BU), from the feces of Gen-treated mice. Only BA played a protective role against ConA-induced liver injury. Further studies demonstrated that BA-reconstituted mice had reduced CD95/CD95L signaling, which was required for the decrease in the L-glutathione/glutathione (GSSG/GSH) ratio observed in the liver. BA-reconstituted mice were also more resistant to alcoholic liver injury. Our work showed that a specific murine intestinal bacterial strain, BA, ameliorated liver injury by reducing hepatocyte apoptosis in a CD95-dependent manner. Determination of the function of BA may provide an opportunity for its future use as a treatment for liver disease.
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Affiliation(s)
- Hesuiyuan Wang
- College of Life Sciences, Nankai University, Tianjin, China
| | - Qing Wang
- College of Life Sciences, Nankai University, Tianjin, China
| | - Chengmao Yang
- College of Life Sciences, Nankai University, Tianjin, China
| | - Mingming Guo
- College of Life Sciences, Nankai University, Tianjin, China
| | - Xiaoyue Cui
- College of Life Sciences, Nankai University, Tianjin, China
| | - Zhe Jing
- College of Life Sciences, Nankai University, Tianjin, China
| | - Yujie Liu
- College of Life Sciences, Nankai University, Tianjin, China
| | - Wanjin Qiao
- College of Life Sciences, Nankai University, Tianjin, China
| | - Hang Qi
- College of Life Sciences, Nankai University, Tianjin, China
| | - Hongyang Zhang
- College of Life Sciences, Nankai University, Tianjin, China
| | - Xu Zhang
- College of Life Sciences, Nankai University, Tianjin, China
| | - Na Zhao
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China
| | - Mengjuan Zhang
- College of Life Sciences, Nankai University, Tianjin, China
| | - Min Chen
- College of Life Sciences, Nankai University, Tianjin, China
| | - Song Zhang
- College of Life Sciences, Nankai University, Tianjin, China
| | - Haijin Xu
- College of Life Sciences, Nankai University, Tianjin, China,The Key Laboratory of Molecular Microbiology and Technology, Ministry of Education, College of Life Sciences, Nankai University, Tianjin, China
| | - Liqing Zhao
- College of Life Sciences, Nankai University, Tianjin, China
| | - Mingqiang Qiao
- College of Life Sciences, Nankai University, Tianjin, China,The Key Laboratory of Molecular Microbiology and Technology, Ministry of Education, College of Life Sciences, Nankai University, Tianjin, China
| | - Zhenzhou Wu
- College of Life Sciences, Nankai University, Tianjin, China,The Key Laboratory of Molecular Microbiology and Technology, Ministry of Education, College of Life Sciences, Nankai University, Tianjin, China,CONTACT Zhenzhou Wu Nankai University, No. 94 Weijin Road, Nankai Distract, Tianjin300071, China
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Sun C, Fujisawa M, Ohara T, Liu Q, Cao C, Yang X, Yoshimura T, Kunkel SL, Matsukawa A. Spred2 controls the severity of Concanavalin A-induced liver damage by limiting interferon-gamma production by CD4 + and CD8 + T cells. J Adv Res 2022; 35:71-86. [PMID: 35003795 PMCID: PMC8721245 DOI: 10.1016/j.jare.2021.03.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Revised: 03/12/2021] [Accepted: 03/30/2021] [Indexed: 11/15/2022] Open
Abstract
Spred2-/- mice developed exacerbated Con A-induced liver damage with increased IFNγ production. MEK/ERK inhibitor U0126 markedly inhibited the damage and reduced IFNγ production. Neutralization of IFNγ abolished the damage with down-regulated hepatic STAT1 activation. Depletion of CD4+/CD8+ T cells improved the damage with decreased IFNγ production. Transplantation of CD4+/CD8+ T cells into RAG1-/- mice reproduced severe liver damage. Liver damage and IFNγ production were significantly lower in Spred2 transgenic mice. Introduction Mitogen-activated protein kinases (MAPKs) are involved in T cell-mediated liver damage. However, the inhibitory mechanism(s) that controls T cell-mediated liver damage remains unknown. Objectives We investigated whether Spred2 (Sprouty-related, EVH1 domain-containing protein 2) that negatively regulates ERK-MAPK pathway has a biological impact on T cell-mediated liver damage by using a murine model. Methods We induced hepatotoxicity in genetically engineered mice by intravenously injecting Concanavalin A (Con A) and analyzed the mechanisms using serum chemistry, histology, ELISA, qRT-PCR, Western blotting and flow cytometry. Results Spred2-deficient mice (Spred2-/-) developed more sever liver damage than wild-type (WT) mice with increased interferon-γ (IFNγ) production. Hepatic ERK phosphorylation was enhanced in Spred2-/- mice, and pretreatment of Spred2-/- mice with the MAPK/ERK inhibitor U0126 markedly inhibited the liver damage and reduced IFNγ production. Neutralization of IFNγ abolished the damage with decreased hepatic Stat1 activation in Spred2-/- mice. IFNγ was mainly produced from CD4+ and CD8+ T cells, and their depletion decreased liver damage and IFNγ production. Transplantation of CD4+ and/or CD8+ T cells from Spred2-/- mice into RAG1-/- mice deficient in both T and B cells caused more severe liver damage than those from WT mice. Hepatic expression of T cell attractants, CXCL9 and CXCL10, was augmented in Spred2-/- mice as compared to WT mice. Conversely, liver damage, IFNγ production and the recruitment of CD4+ and CD8+ T cells in livers after Con A challenge were lower in Spred2 transgenic mice, and Spred2-overexpressing CD4+ and CD8+ T cells produced lower levels of IFNγ than WT cells upon stimulation with Con A in vitro. Conclusion We demonstrated, for the first time, that Spred2 functions as an endogenous regulator of T cell IFNγ production and Spred2-mediated inhibition of ERK-MAPK pathway may be an effective remedy for T cell-dependent liver damage.
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Affiliation(s)
- Cuiming Sun
- Department of Pathology and Experimental Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.,Department of Infectious Disease, The First Hospital of China Medical University, Liaoning, China
| | - Masayoshi Fujisawa
- Department of Pathology and Experimental Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Toshiaki Ohara
- Department of Pathology and Experimental Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Qiuying Liu
- Department of Pathology and Experimental Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Chen Cao
- Department of Pathology and Experimental Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Xu Yang
- Department of Pathology and Experimental Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Teizo Yoshimura
- Department of Pathology and Experimental Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Steven L Kunkel
- Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Akihiro Matsukawa
- Department of Pathology and Experimental Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
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30
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Hao J, Sun W, Xu H. Pathogenesis of Concanavalin A induced autoimmune hepatitis in mice. Int Immunopharmacol 2021; 102:108411. [PMID: 34891001 DOI: 10.1016/j.intimp.2021.108411] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 11/05/2021] [Accepted: 11/24/2021] [Indexed: 12/11/2022]
Abstract
Autoimmune hepatitis (AIH) is an autoimmune disease characterized by liver parenchymal destruction and chronic fibrosis. Its exact etiology and pathogenesis are not yet fully understood.(Please connect with the following, do not leave a line) Concanavalin A (Con A)-induced mice hepatitis model is a liver injury mediated by T cell and macrophage activation, and its pathogenesis and pathological changes are similar to human AIH. The establishment of this model has greatly promoted the research progress of AIH pathogenesis. However, the exact mechanism of Con A induced liver injury in mice, and its possible defects or deficiencies, has not yet been described in a clear and detailed manner. Therefore, the model has some limitations when applied to the study of the pathogenesis and treatment mechanism of AIH. This article reveals the pathogenesis of Con A induced liver injury in mice from the aspects of immune disorder and coagulation mechanism, expounds the significance of non-coding RNA in this model, summarizes the signal transduction pathways involved in this model, and summarizes the advantages and disadvantages of the model, which provides a theoretical basis and research target for the application of Con A induced liver injury model in AIH in the future.
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Affiliation(s)
- Jianheng Hao
- Basic Laboratory of Integrated Traditional Chinese and Western Medicine, Shanxi University of Traditional Chinese Medicine, Jinzhong 030619, China.
| | - Weili Sun
- Basic Laboratory of Integrated Traditional Chinese and Western Medicine, Shanxi University of Traditional Chinese Medicine, Jinzhong 030619, China
| | - Huichao Xu
- Acupuncture and Massage Laboratory, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, China
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31
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Nguyen LN, Nguyen LNT, Zhao J, Schank M, Dang X, Cao D, Khanal S, Thakuri BKC, Zhang J, Lu Z, Wu XY, El Gazzar M, Ning S, Wang L, Moorman JP, Yao ZQ. Immune Activation Induces Telomeric DNA Damage and Promotes Short-Lived Effector T Cell Differentiation in Chronic HCV Infection. Hepatology 2021; 74:2380-2394. [PMID: 34110660 PMCID: PMC8542603 DOI: 10.1002/hep.32008] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Revised: 05/10/2021] [Accepted: 06/01/2021] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIMS Hepatitis C virus (HCV) leads to a high rate of chronic infection and T cell dysfunction. Although it is well known that chronic antigenic stimulation is a driving force for impaired T cell functions, the precise mechanisms underlying immune activation-induced T cell dysfunctions during HCV infection remain elusive. APPROACH AND RESULTS Here, we demonstrated that circulating CD4+ T cells from patients who are chronically HCV-infected exhibit an immune activation status, as evidenced by the overexpression of cell activation markers human leukocyte antigen-antigen D-related, glucose transporter 1, granzyme B, and the short-lived effector marker CD127- killer cell lectin-like receptor G1+ . In contrast, the expression of stem cell-like transcription factor T cell factor 1 and telomeric repeat-binding factor 2 (TRF2) are significantly reduced in CD4+ T cells from patients who are chronically HCV-infected compared with healthy participants (HP). Mechanistic studies revealed that CD4+ T cells from participants with HCV exhibit phosphoinositide 3-kinase/Akt/mammalian target of rapamycin signaling hyperactivation on T cell receptor stimulation, promoting proinflammatory effector cell differentiation, telomeric DNA damage, and cellular apoptosis. Inhibition of Akt signaling during T cell activation preserved the precursor memory cell population and prevented inflammatory effector cell expansion, DNA damage, and apoptotic death. Moreover, knockdown of TRF2 reduced HP T cell stemness and triggered telomeric DNA damage and cellular apoptosis, whereas overexpression of TRF2 in CD4 T cells prevented telomeric DNA damage. CONCLUSIONS These results suggest that modulation of immune activation through inhibiting Akt signaling and protecting telomeres through enhancing TRF2 expression may open therapeutic strategies to fine tune the adaptive immune responses in the setting of persistent immune activation and inflammation during chronic HCV infection.
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Affiliation(s)
- Lam Nhat Nguyen
- Center of Excellence in Inflammation, Infectious Disease and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN.,Department of Internal Medicine, Division of Infectious, Inflammatory and Immunologic Diseases, Quillen College of Medicine, ETSU, Johnson City, TN
| | - Lam Ngoc Thao Nguyen
- Center of Excellence in Inflammation, Infectious Disease and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN.,Department of Internal Medicine, Division of Infectious, Inflammatory and Immunologic Diseases, Quillen College of Medicine, ETSU, Johnson City, TN
| | - Juan Zhao
- Center of Excellence in Inflammation, Infectious Disease and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN.,Department of Internal Medicine, Division of Infectious, Inflammatory and Immunologic Diseases, Quillen College of Medicine, ETSU, Johnson City, TN
| | - Madison Schank
- Center of Excellence in Inflammation, Infectious Disease and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN.,Department of Internal Medicine, Division of Infectious, Inflammatory and Immunologic Diseases, Quillen College of Medicine, ETSU, Johnson City, TN
| | - Xindi Dang
- Center of Excellence in Inflammation, Infectious Disease and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN.,Department of Internal Medicine, Division of Infectious, Inflammatory and Immunologic Diseases, Quillen College of Medicine, ETSU, Johnson City, TN
| | - Dechao Cao
- Center of Excellence in Inflammation, Infectious Disease and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN.,Department of Internal Medicine, Division of Infectious, Inflammatory and Immunologic Diseases, Quillen College of Medicine, ETSU, Johnson City, TN
| | - Sushant Khanal
- Center of Excellence in Inflammation, Infectious Disease and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN.,Department of Internal Medicine, Division of Infectious, Inflammatory and Immunologic Diseases, Quillen College of Medicine, ETSU, Johnson City, TN
| | - Bal Krishna Chand Thakuri
- Center of Excellence in Inflammation, Infectious Disease and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN.,Department of Internal Medicine, Division of Infectious, Inflammatory and Immunologic Diseases, Quillen College of Medicine, ETSU, Johnson City, TN
| | - Jinyu Zhang
- Center of Excellence in Inflammation, Infectious Disease and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN.,Department of Internal Medicine, Division of Infectious, Inflammatory and Immunologic Diseases, Quillen College of Medicine, ETSU, Johnson City, TN
| | - Zeyuan Lu
- Center of Excellence in Inflammation, Infectious Disease and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN.,Department of Internal Medicine, Division of Infectious, Inflammatory and Immunologic Diseases, Quillen College of Medicine, ETSU, Johnson City, TN
| | - Xiao Y Wu
- Center of Excellence in Inflammation, Infectious Disease and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN.,Department of Internal Medicine, Division of Infectious, Inflammatory and Immunologic Diseases, Quillen College of Medicine, ETSU, Johnson City, TN
| | - Mohamed El Gazzar
- Center of Excellence in Inflammation, Infectious Disease and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN.,Department of Internal Medicine, Division of Infectious, Inflammatory and Immunologic Diseases, Quillen College of Medicine, ETSU, Johnson City, TN
| | - Shunbin Ning
- Center of Excellence in Inflammation, Infectious Disease and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN.,Department of Internal Medicine, Division of Infectious, Inflammatory and Immunologic Diseases, Quillen College of Medicine, ETSU, Johnson City, TN
| | - Ling Wang
- Center of Excellence in Inflammation, Infectious Disease and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN.,Department of Internal Medicine, Division of Infectious, Inflammatory and Immunologic Diseases, Quillen College of Medicine, ETSU, Johnson City, TN
| | - Jonathan P Moorman
- Center of Excellence in Inflammation, Infectious Disease and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN.,Department of Internal Medicine, Division of Infectious, Inflammatory and Immunologic Diseases, Quillen College of Medicine, ETSU, Johnson City, TN.,Hepatitis (HCV/HBV/HIV) Program, James H. Quillen VA Medical Center, Department of Veterans Affairs, Johnson City, TN
| | - Zhi Q Yao
- Center of Excellence in Inflammation, Infectious Disease and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN.,Department of Internal Medicine, Division of Infectious, Inflammatory and Immunologic Diseases, Quillen College of Medicine, ETSU, Johnson City, TN.,Hepatitis (HCV/HBV/HIV) Program, James H. Quillen VA Medical Center, Department of Veterans Affairs, Johnson City, TN
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Shen Y, Cingolani F, Malik SA, Wen J, Liu Y, Czaja MJ. Sex-Specific Regulation of Interferon-γ Cytotoxicity in Mouse Liver by Autophagy. Hepatology 2021; 74:2745-2758. [PMID: 34118081 PMCID: PMC8542567 DOI: 10.1002/hep.32010] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 05/18/2021] [Accepted: 06/09/2021] [Indexed: 12/22/2022]
Abstract
BACKGROUND AND AIMS Interferon-γ (IFNγ) is a central activator of immune responses in the liver and other organs. IFNγ triggers tissue injury and inflammation in immune diseases, which occur predominantly in females for unknown reasons. Recent findings that autophagy regulates hepatotoxicity from proinflammatory cytokines led to an examination of whether defective hepatocyte autophagy underlies sex-specific liver injury and inflammation induced by IFNγ. APPROACH AND RESULTS A lentiviral autophagy-related 5 (Atg5) knockdown was performed to decrease autophagy-sensitized alpha mouse liver (AML 12) hepatocytes to death from IFNγ in combination with IL-1β or TNF. Death was necrosis attributable to impaired energy homeostasis and adenosine triphosphate depletion. Male mice with decreased autophagy from a tamoxifen-inducible, hepatocyte-specific Atg5 knockout were resistant to IFNγ hepatotoxicity whereas female knockout mice developed liver injury and inflammation. Female mice had increased IFNγ-induced signal transducer and activator of transcription 1 (STAT1) levels compared to males. Blocking STAT1, but not interferon regulatory factor 1, signaling prevented IFNγ-induced hepatocyte death in autophagy-deficient AML12 cells and female mice. The mechanism of death is STAT1-induced overexpression of nitric oxide synthase 2 (NOS2) as in vitro hepatocyte death and in vivo liver injury were blocked by NOS2 inhibition. CONCLUSIONS Decreased hepatocyte autophagy sensitizes mice to IFNγ-induced liver injury and inflammation through overactivation of STAT1 signaling that causes NOS2 overexpression. Hepatotoxicity is restricted to female mice, suggesting that sex-specific effects of defective autophagy may underlie the increased susceptibility of females to IFNγ-mediated immune diseases.
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Affiliation(s)
- Yang Shen
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA
| | - Francesca Cingolani
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA
| | - Shoaib Ahmad Malik
- Department of Biochemistry, Sargodha Medical College, Sargodha, Pakistan
| | - Jing Wen
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA
| | - Yunshan Liu
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA
| | - Mark J. Czaja
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA
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Wang H, Zhao Y, Ren B, Qin Y, Li G, Kong D, Qin H, Hao J, Sun D, Wang H. Endometrial regenerative cells with galectin-9 high-expression attenuate experimental autoimmune hepatitis. Stem Cell Res Ther 2021; 12:541. [PMID: 34654474 PMCID: PMC8518235 DOI: 10.1186/s13287-021-02604-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Accepted: 09/23/2021] [Indexed: 12/15/2022] Open
Abstract
Background Autoimmune hepatitis (AIH) is a T cell-mediated immune disease that activates abnormally against hepatic antigens. We have previously reported that endometrial regenerative cells (ERCs) were a novel source of adult stem cells, which exhibiting with powerful immunomodulatory effects. Galectin-9 (Gal-9) is expressed in ERCs and plays an important role in regulating T cell response. This study aims to explore the role of ERCs in attenuation of AIH and to determine the potential mechanism of Gal-9 in ERC-mediated immune regulation. Methods ERCs were obtained from menstrual blood of healthy female volunteers. In vitro, ERCs were transfected with lentivirus vectors carrying LGALS9 gene and encoding green fluoresce protein (GFP-Gal-9-LVs) at a MOI 50, Gal-9 expression in ERCs was detected by ELISA and Q-PCR. CD4+ T cells isolated from C57BL/6 mouse spleen were co-cultured with ERCs. The proliferation of CD4+ T cells was detected by CCK-8 kit and the level of Lck/zap-70/LAT protein was measured by western blot. Furthermore, AIH was induced by ConA in C57BL/6 mice which were randomly assigned to untreated, unmodified ERC-treated and Gal-9 high-expressing ERC-treated groups. Histopathological score, liver function, CD4+/CD8+ cell infiltration in liver tissues, the proportion of immune cells in the spleen and liver, and ERC tracking were performed accordingly to assess the progression degree of AIH. Results After transfecting with GFP-Gal-9-LVs, Gal-9 expression in ERCs was significantly increased. Additionally, Gal-9 high-expressing ERCs effectively inhibited CD4+ T cell proliferation and downregulated CD4+ T cell active related proteins p-Lck/p-ZAP70/p-LAT in vitro. Furthermore, treatment with Gal-9 high-expressing ERCs restored liver function, ameliorated liver pathological damage, inhibit CD4+ and CD8+ T cell proliferation and suppress Th1 and Th17 cell response in the hepatitis mice. In addition, Gal-9 high-expressing ERCs further markedly enhanced the level of IL-10 but reduced the levels of IFN-γ, TNF-α, and IL-4 in mouse sera and liver. Cell tracking also showed that ERCs could migrate to the damaged liver organs. Conclusions The results suggested that Gal-9 was an essential modulator, which was required by ERCs in regulating T cell response and attenuating ConA-induced experimental hepatitis. And also, it provides a novel idea for the clinical treatment of AIH.
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Affiliation(s)
- Hongda Wang
- Department of General Surgery, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, China.,Tianjin General Surgery Institute, Tianjin, China
| | - Yiming Zhao
- Department of General Surgery, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, China.,Tianjin General Surgery Institute, Tianjin, China.,Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Bingbing Ren
- Department of Pediatric Surgery, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, China
| | - Yafei Qin
- Department of General Surgery, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, China.,Tianjin General Surgery Institute, Tianjin, China
| | - Guangming Li
- Department of General Surgery, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, China.,Tianjin General Surgery Institute, Tianjin, China
| | - Dejun Kong
- Department of General Surgery, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, China.,Tianjin General Surgery Institute, Tianjin, China
| | - Hong Qin
- Department of General Surgery, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, China.,Tianjin General Surgery Institute, Tianjin, China
| | - Jingpeng Hao
- Tianjin General Surgery Institute, Tianjin, China.,Department of Anorectal Surgery, The Second Hospital of Tianjin Medical University, Tianjin, China
| | - Daqing Sun
- Department of Pediatric Surgery, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, China.
| | - Hao Wang
- Department of General Surgery, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, China. .,Tianjin General Surgery Institute, Tianjin, China.
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Huganbuzure Granule Attenuates Concanavalin-A-Induced Immune Liver Injury in Mice via Regulating the Balance of Th1/Th2/Th17/Treg Cells and Inhibiting Apoptosis. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2021; 2021:5578021. [PMID: 34539800 PMCID: PMC8443346 DOI: 10.1155/2021/5578021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 07/30/2021] [Accepted: 08/16/2021] [Indexed: 11/23/2022]
Abstract
In Uygur medicine, Huganbuzure granule (HBG) is one of the classical prescriptions for liver protection. However, its role in immune liver injury remains unknown. This study evaluates the effect of HBG on concanavalin-A- (ConA-) induced immune liver injury and investigates its protective underlying mechanism. BALB/c mice were randomly divided into five groups (n = 24 mice per group): control, ConA, 1.6 g/kg HBG + ConA, 3.2 g/kg HBG + ConA, and 6 mg/kg prednisolone + ConA. HBG was intragastrically administrated once daily for ten consecutive days, prior to ConA (20 mg/kg) injection. The levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), superoxide dismutase (SOD), and malondialdehyde (MDA) in mouse serum were measured after ConA injection. Moreover, liver-related mRNA levels were evaluated by qPCR. The detection of liver-related proteins was assessed by immunohistochemistry and western blot analysis. Compared with the ConA group, HBG reduced the mRNA expression of IL-17A and IFN-γ and the protein expression of T-bet and ROR-γt. In addition, HBG increased the mRNA expression of IL-4 and TGF-β and protein expression of GATA3 and Foxp3, indicating that HBG regulated the balance of Th1/Th2 and Th17/Treg. Furthermore, HBG alleviated immune liver injury by reducing oxidative stress, inhibiting apoptosis, and decreasing the expression of p-JNK, p-ERK, p-p38, p-JAK1, p-STAT1, p-STAT3, and IRF1. Our data suggested that HBG attenuated ConA-induced immune liver injury by regulating the immune balance and inhibiting JAK1/STATs/IRF1 signaling, thereby reducing apoptosis induced by JNK activation. The findings indicate that HBG may be a promising drug for immune liver injury.
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Pan L, Liu C, Liu Q, Li Y, Du C, Kang X, Dong S, Zhou Z, Chen H, Liang X, Chu J, Xu Y, Zhang Q. Human Wharton's jelly-derived mesenchymal stem cells alleviate concanavalin A-induced fulminant hepatitis by repressing NF-κB signaling and glycolysis. Stem Cell Res Ther 2021; 12:496. [PMID: 34503553 PMCID: PMC8427901 DOI: 10.1186/s13287-021-02560-x] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Accepted: 08/20/2021] [Indexed: 02/08/2023] Open
Abstract
Background Fulminant hepatitis is a severe life-threatening clinical condition with rapid progressive loss of liver function. It is characterized by massive activation and infiltration of immune cells into the liver and disturbance of inflammatory cytokine production. Mesenchymal stem cells (MSCs) showed potent immunomodulatory properties. Transplantation of MSCs is suggested as a promising therapeutic approach for a host of inflammatory conditions. Methods In the current study, a well-established concanavalin A (Con A)-induced fulminant hepatitis mouse model was used to investigate the effects of transplanting human umbilical cord Wharton's jelly-derived MSCs (hWJ-MSCs) on fulminant hepatitis. Results We showed that hWJ-MSCs effectively alleviate fulminant hepatitis in mouse models, primarily through inhibiting T cell immunity. RNA sequencing of liver tissues and human T cells co-cultured with hWJ-MSCs showed that NF-κB signaling and glycolysis are two main pathways mediating the protective role of hWJ-MSCs on both Con A-induced hepatitis in vivo and T cell activation in vitro. Conclusion In summary, our data confirmed the potent therapeutic role of MSCs-derived from Wharton's jelly of human umbilical cord on Con A-induced fulminant hepatitis, and uncovered new mechanisms that glycolysis metabolic shift mediates suppression of T cell immunity by hWJ-MSCs. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-021-02560-x.
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Affiliation(s)
- Lijie Pan
- Biotherapy Center, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510630, China.,Cell-Gene Therapy Translational Medicine Research Centre, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Chang Liu
- Biotherapy Center, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510630, China.,Cell-Gene Therapy Translational Medicine Research Centre, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Qiuli Liu
- Biotherapy Center, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510630, China.,Cell-Gene Therapy Translational Medicine Research Centre, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Yanli Li
- Biotherapy Center, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510630, China
| | - Cong Du
- Biotherapy Center, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510630, China
| | - Xinmei Kang
- Biotherapy Center, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510630, China
| | - Shuai Dong
- Biotherapy Center, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510630, China
| | - Zhuowei Zhou
- Biotherapy Center, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510630, China
| | - Huaxin Chen
- Biotherapy Center, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510630, China
| | - Xiaoqi Liang
- Biotherapy Center, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510630, China
| | - Jiajie Chu
- Biotherapy Center, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510630, China
| | - Yan Xu
- Biotherapy Center, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510630, China.
| | - Qi Zhang
- Biotherapy Center, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510630, China. .,Cell-Gene Therapy Translational Medicine Research Centre, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China. .,Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
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Yamaguchi A, Teratani T, Chu P, Suzuki T, Taniki N, Mikami Y, Shiba S, Morikawa R, Amiya T, Aoki R, Kanai T, Nakamoto N. Hepatic Adenosine Triphosphate Reduction Through the Short-Chain Fatty Acids-Peroxisome Proliferator-Activated Receptor γ-Uncoupling Protein 2 Axis Alleviates Immune-Mediated Acute Hepatitis in Inulin-Supplemented Mice. Hepatol Commun 2021; 5:1555-1570. [PMID: 34510840 PMCID: PMC8435281 DOI: 10.1002/hep4.1742] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 04/08/2021] [Accepted: 04/24/2021] [Indexed: 02/04/2023] Open
Abstract
How liver tolerance is disrupted in immune-mediated liver injury is currently unclear. There is also insufficient information available regarding susceptibility, precipitation, escalation, and perpetuation of autoimmune hepatitis. To explore how dietary fiber influences hepatic damage, we applied the concanavalin A (ConA)-induced acute immune-mediated liver injury model in mice fed a diet supplemented with 6.8% inulin, a water-soluble fermentable fiber. Twelve hours after ConA administration, inulin-supplemented diet-fed mice demonstrated significantly alleviated hepatic damage histologically and serologically, with down-regulation of hepatic interferon-γ and tumor necrosis factor and reduced myeloperoxidase (MPO)-producing neutrophil infiltration. Preconditioning with an inulin-supplemented diet for 2 weeks significantly reduced hepatic adenosine triphosphate (ATP) content; suramin, a purinergic P2 receptor antagonist, abolished the protective effect. Of note, the portal plasma derived from mice fed the inulin-supplemented diet significantly alleviated ConA-induced immune-mediated liver injury. Mechanistically, increased portal short-chain fatty acid (SCFA) levels, such as those of acetate and butyrate, by inulin supplementation leads to up-regulation of hepatic γ-type peroxisome proliferator-activated receptor (Pparg) and uncoupling protein 2 (Ucp2), which uncouples mitochondrial ATP synthesis downstream of PPARγ. Pparg down-regulating small interfering RNA cancelled the protective effect of inulin supplementation against MPO-producing neutrophil infiltration and the subsequent immune-mediated liver injury, suggesting that the SCFA-PPARγ-UCP2 axis plays a key role in the protective effect by inulin supplementation. Moreover, significant changes in the gut microbiota, including increased operational taxonomic units in genera Akkermansia and Allobaculum, also characterized the protective effect of the inulin-supplemented diet. Conclusion: There is a possible unraveled etiopathophysiological link between the maintenance of liver tolerance and dietary fiber. The SCFA-PPARγ-UCP2 axis may provide therapeutic targets for immune-mediated liver injury in the future.
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Affiliation(s)
- Akihiro Yamaguchi
- Division of Gastroenterology and HepatologyDepartment of Internal MedicineKeio University School of MedicineTokyoJapan
- Department of Gastroenterology and HepatologyNational Hospital Organization Saitama HospitalSaitamaJapan
| | - Toshiaki Teratani
- Division of Gastroenterology and HepatologyDepartment of Internal MedicineKeio University School of MedicineTokyoJapan
| | - Po‐sung Chu
- Division of Gastroenterology and HepatologyDepartment of Internal MedicineKeio University School of MedicineTokyoJapan
| | - Takahiro Suzuki
- Division of Gastroenterology and HepatologyDepartment of Internal MedicineKeio University School of MedicineTokyoJapan
- Miyarisan Pharmaceutical Co., Ltd.TokyoJapan
| | - Nobuhito Taniki
- Division of Gastroenterology and HepatologyDepartment of Internal MedicineKeio University School of MedicineTokyoJapan
| | - Yohei Mikami
- Division of Gastroenterology and HepatologyDepartment of Internal MedicineKeio University School of MedicineTokyoJapan
| | - Shunsuke Shiba
- Division of Gastroenterology and HepatologyDepartment of Internal MedicineKeio University School of MedicineTokyoJapan
| | - Rei Morikawa
- Division of Gastroenterology and HepatologyDepartment of Internal MedicineKeio University School of MedicineTokyoJapan
| | - Takeru Amiya
- Division of Gastroenterology and HepatologyDepartment of Internal MedicineKeio University School of MedicineTokyoJapan
- Research Unit/Immunology and InflammationSohyaku Innovative Research DivisionMitsubishi Tanabe Pharma CoKanagawaJapan
| | - Ryo Aoki
- Division of Gastroenterology and HepatologyDepartment of Internal MedicineKeio University School of MedicineTokyoJapan
- Institute of Health ScienceEzaki Glico Co., Ltd.OsakaJapan
| | - Takanori Kanai
- Division of Gastroenterology and HepatologyDepartment of Internal MedicineKeio University School of MedicineTokyoJapan
| | - Nobuhiro Nakamoto
- Division of Gastroenterology and HepatologyDepartment of Internal MedicineKeio University School of MedicineTokyoJapan
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Li G, Kong D, Qin Y, Wang H, Hu Y, Zhao Y, Hao J, Qin H, Yu D, Zhu Y, Sun C, Wang H. IL-37 overexpression enhances the therapeutic effect of endometrial regenerative cells in concanavalin A-induced hepatitis. Cytotherapy 2021; 23:617-626. [PMID: 33593687 DOI: 10.1016/j.jcyt.2020.12.006] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Revised: 12/06/2020] [Accepted: 12/21/2020] [Indexed: 11/28/2022]
Abstract
BACKGROUND AIMS Mesenchymal stromal cells and immunosuppressive factor IL-37 can both suppress concanavalin A (Con A)-induced hepatitis in mice. Endometrial regenerative cells (ERCs), novel types of mesenchymal-like stromal cells, possess powerful immunomodulatory effects and are effective in treating various diseases. The aim of this study was to explore the effects of ERCs in suppressing Con A-induced hepatitis and determine whether IL-37 overexpression could enhance the therapeutic effect of ERCs in this process. METHODS ERCs were extracted from the menstrual blood of healthy female volunteer donors. The IL-37 gene was transferred into ERCs, and the expression of IL-37 in cells was detected by western blot and enzyme-linked immunosorbent assay. Hepatitis was induced by Con A in C57BL/6 mice that were randomly divided into groups treated with phosphate-buffered saline, ERCs, IL-37 or ERCs transfected with the IL-37 gene (IL-37-ERCs). Cell tracking, liver function, histopathological and immunohistological changes, immune cell proportions and levels of cytokines were measured 24 h after Con A administration. RESULTS Compared with ERC or IL-37 treatment, IL-37-ERCs further reduced levels of liver enzymes (alanine aminotransferase and aspartate aminotransferase) and improved histopathological changes in the liver. In addition, IL-37-ERC treatment further reduced the proportions of M1 macrophages and CD4+ T cells and increased the proportion of regulatory T cells. Moreover, IL-37-ERC treatment resulted in lower levels of IL-12 and interferon gamma, and higher level of transforming growth factor beta. CONCLUSIONS The results of this study suggest that ERCs can effectively alleviate Con A-induced hepatitis. Furthermore, IL-37 overexpression can significantly enhance the therapeutic efficacy of ERCs by augmenting the immunomodulatory and anti-inflammatory properties of ERCs. This study may provide a promising strategy for treatment of T-cell-dependent hepatitis.
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Affiliation(s)
- Guangming Li
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China; Tianjin General Surgery Institute, Tianjin, China
| | - Dejun Kong
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China; Tianjin General Surgery Institute, Tianjin, China
| | - Yafei Qin
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China; Tianjin General Surgery Institute, Tianjin, China
| | - Hongda Wang
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China; Tianjin General Surgery Institute, Tianjin, China
| | - Yonghao Hu
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China; Tianjin General Surgery Institute, Tianjin, China
| | - Yiming Zhao
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China; Tianjin General Surgery Institute, Tianjin, China
| | - Jingpeng Hao
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China; Tianjin General Surgery Institute, Tianjin, China
| | - Hong Qin
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China; Tianjin General Surgery Institute, Tianjin, China
| | - Dingding Yu
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China; Tianjin General Surgery Institute, Tianjin, China
| | - Yanglin Zhu
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China; Tianjin General Surgery Institute, Tianjin, China
| | - Chenglu Sun
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China; Tianjin General Surgery Institute, Tianjin, China
| | - Hao Wang
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China; Tianjin General Surgery Institute, Tianjin, China.
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Hepatoprotective Effect of Mixture of Dipropyl Polysulfides in Concanavalin A-Induced Hepatitis. Nutrients 2021; 13:nu13031022. [PMID: 33809904 PMCID: PMC8004208 DOI: 10.3390/nu13031022] [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: 02/08/2021] [Revised: 03/08/2021] [Accepted: 03/13/2021] [Indexed: 12/15/2022] Open
Abstract
The main biologically active components of plants belonging to the genus Allium, responsible for their biological activities, including anti-inflammatory, antioxidant and immunomodulatory, are organosulfur compounds. The aim of this study was to synthetize the mixture of dipropyl polysulfides (DPPS) and to test their biological activity in acute hepatitis. C57BL/6 mice were administered orally with DPPS 6 h before intravenous injection of Concanavalin A (ConA). Liver inflammation, necrosis and hepatocytes apoptosis were determined by histological analyses. Cytokines in liver tissue were determined by ELISA, expression of adhesive molecules and enzymes by RT PCR, while liver mononuclear cells were analyzed by flow cytometry. DPPS pretreatment significantly attenuated liver inflammation and injury, as evidenced by biochemical and histopathological observations. In DPPS-pretreated mice, messenger RNA levels of adhesion molecules and NADPH oxidase complex were significantly reduced, while the expression of SOD enzymes was enhanced. DPPS pretreatment decreased protein level of inflammatory cytokines and increased percentage of T regulatory cells in the livers of ConA mice. DPPS showed hepatoprotective effects in ConA-induced hepatitis, characterized by attenuation of inflammation and affection of Th17/Treg balance in favor of T regulatory cells and implicating potential therapeutic usage of DPPS mixture in inflammatory liver diseases.
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Li Y, Gong L, Weng L, Pan X, Liu C, Li M. Interleukin-39 exacerbates concanavalin A-induced liver injury. Immunopharmacol Immunotoxicol 2021; 43:94-99. [PMID: 33412981 DOI: 10.1080/08923973.2020.1869778] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
BACKGROUND Interleukin (IL)-39 is a novel member of IL-12 family and has been reported to play a pro-inflammatory role in lupus-like mice, but its function in concanavalin A (ConA)-induced liver injury is currently unclear. MATERIALS AND METHODS In this study, we investigated the effects of IL-39 expression in a mouse model of ConA induced-hepatitis. We first showed that delivery of plasmid DNA encoding mouse IL-39 using the hydrodynamic tail vein injection method increased IL-39 mRNA and protein levels in the liver. We then administrated mice with IL-39 plasmid before ConA injection and measured serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, inflammatory infiltration, and hepatocyte necrosis in the liver. Additionally, we further explored the potential mechanism of IL-39 in ConA-induced liver injury by measuring several inflammatory mediators. RESULTS We found that ectopic IL-39 expression promoted the ConA-induced increase in serum ALT and AST levels, inflammatory infiltration, and hepatocyte necrosis in the liver. We also observed that IL-39 plasmid administration significantly increased serum and liver interferon-γ, tumor necrosis factor-α, and IL-17A levels, but did not affect serum and liver IL-10 levels in ConA-induced hepatitis. CONCLUSION Our results suggest that IL-39 can exacerbate ConA-induced hepatitis and may be a therapeutic target in inflammatory liver disease.
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Affiliation(s)
- Yan Li
- The Affiliated Hospital of Medical School of Ningbo University, and Department of Immunology, Ningbo University School of Medicine, Ningbo, China
| | - Luping Gong
- The Affiliated Hospital of Medical School of Ningbo University, and Department of Immunology, Ningbo University School of Medicine, Ningbo, China.,School of Marine Sciences, Ningbo University, Ningbo, China
| | - Linjie Weng
- The Affiliated Hospital of Medical School of Ningbo University, and Department of Immunology, Ningbo University School of Medicine, Ningbo, China.,School of Marine Sciences, Ningbo University, Ningbo, China
| | - Xiuhe Pan
- The Affiliated Hospital of Medical School of Ningbo University, and Department of Immunology, Ningbo University School of Medicine, Ningbo, China
| | - Chaobo Liu
- The Affiliated Hospital of Medical School of Ningbo University, and Department of Immunology, Ningbo University School of Medicine, Ningbo, China
| | - Mingcai Li
- The Affiliated Hospital of Medical School of Ningbo University, and Department of Immunology, Ningbo University School of Medicine, Ningbo, China
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Schippers A, Hübel J, Heymann F, Clahsen T, Eswaran S, Schlepütz S, Püllen R, Gaßler N, Tenbrock K, Tacke F, Wagner N. MAdCAM-1/α4β7 Integrin-Mediated Lymphocyte/Endothelium Interactions Exacerbate Acute Immune-Mediated Hepatitis in Mice. Cell Mol Gastroenterol Hepatol 2020; 11:1227-1250.e1. [PMID: 33316453 PMCID: PMC8053699 DOI: 10.1016/j.jcmgh.2020.12.003] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Revised: 12/03/2020] [Accepted: 12/04/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Aberrant lymphocyte homing could potentially link inflammatory processes in the intestine and the liver, as distinct hepatobiliary diseases frequently develop as extra-intestinal manifestations in inflammatory bowel disease. In this study, we examined the role of the gut-tropic leukocyte adhesion molecule β7 integrin and its endothelial ligand mucosal addressin cell-adhesion molecule-1 (MAdCAM-1) in immune-mediated hepatitis in mice. METHODS Wild-type (WT) mice, MAdCAM-1-deficient mice, β7 integrin-deficient mice, RAG-2-deficient mice, RAG-2/MAdCAM-1 double-deficient mice, and RAG-2/β7 integrin double-deficient mice were subjected to concanavalin A (ConA)-induced hepatitis. The degree of hepatitis was evaluated by histology, flow cytometry, and expression analysis of inflammatory mediators. The motility of lymphocytes in progressive liver damage was assessed by intravital laser scanning multiphoton microscopy. RESULTS Ablation of MAdCAM-1 or β7 integrin ameliorated ConA-induced hepatitis in mice. β7 integrin-deficient lymphocytes caused less liver damage than WT lymphocytes in ConA-treated RAG-2-deficient mice. Moreover, WT lymphocytes caused less liver damage in ConA-treated RAG-2/β7 integrin double-deficient mice than in similarly treated RAG-2-deficient mice, indicating that β7 integrin expression contributes significantly to the liver damage mediated by innate immune cells. MAdCAM-1 expression was dependent on β7 integrin expression on adaptive and innate immune cells. Most importantly, lymphocytes in ConA-treated MAdCAM-1-deficient mice displayed more motility and less adhesion in the liver sinusoids in vivo, than lymphocytes in similarly treated WT mice. CONCLUSIONS These data suggest that β7 integrin expression on lymphocytes and innate immune cells contributes to MAdCAM-1 upregulation and liver damage in acute immune-mediated hepatitis, most likely by facilitating lymphocyte/sinusoidal endothelial cell interactions.
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Affiliation(s)
- Angela Schippers
- Department of Pediatrics, Medical Faculty, RWTH Aachen University, Aachen, Germany
| | - Jessica Hübel
- Department of Pediatrics, Medical Faculty, RWTH Aachen University, Aachen, Germany
| | - Felix Heymann
- Department of Hepatology and Gastroenterology, Charité University Medicine Berlin, Berlin, Germany
| | - Thomas Clahsen
- Department of Pediatrics, Medical Faculty, RWTH Aachen University, Aachen, Germany
| | - Sreepradha Eswaran
- Department of Pediatrics, Medical Faculty, RWTH Aachen University, Aachen, Germany
| | - Sarah Schlepütz
- Department of Pediatrics, Medical Faculty, RWTH Aachen University, Aachen, Germany
| | - Robin Püllen
- Department of Pediatrics, Medical Faculty, RWTH Aachen University, Aachen, Germany
| | - Nikolaus Gaßler
- Institute of Forensic Medicine, Section of Pathology, Jena University Hospital, Jena, Germany
| | - Klaus Tenbrock
- Department of Pediatrics, Medical Faculty, RWTH Aachen University, Aachen, Germany
| | - Frank Tacke
- Department of Hepatology and Gastroenterology, Charité University Medicine Berlin, Berlin, Germany
| | - Norbert Wagner
- Department of Pediatrics, Medical Faculty, RWTH Aachen University, Aachen, Germany.
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Type 1 innate lymphoid cells: Soldiers at the front line of immunity. Biomed J 2020; 44:115-122. [PMID: 33839081 PMCID: PMC8178574 DOI: 10.1016/j.bj.2020.10.001] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Accepted: 10/04/2020] [Indexed: 12/17/2022] Open
Abstract
Innate lymphoid cells (ILCs) are tissue-resident innate lymphocytes that have functions to protect the hosts against pathogens and that regulate tissue inflammation and homeostasis. ILC subsets rapidly produce particular cytokines in response to infection, inflammation, and tissue injury at the local environment. Type 1 ILCs (ILC1s) promptly and abundantly produce interferon (IFN)-γ but lack appreciable cytotoxic activity. ILC1s share many phenotypic, developmental, and functional characteristics with natural killer (NK) cells, which are circulating innate lymphocytes with potent natural cytotoxicity. However, recent studies have established ILC1s as distinct from NK cells. ILC1s predominantly reside in the liver—they initially were discovered as a liver-resident ILC subset—as well as in other lymphoid and non-lymphoid tissues. Accumulating evidence has demonstrated that ILC1s play an important and unique role in host protection and in immunomodulation in their resident organs. However, the pathophysiological role of tissue-resident ILC1s remains largely unclear. In this review, we summarize emerging evidence showing that ILC1s not only contribute to inflammation to protect against pathogens but also promote tissue protection and metabolism. We highlight a unique function of ILC1s in their resident tissues.
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Liu SP, Bian ZH, Zhao ZB, Wang J, Zhang W, Leung PSC, Li L, Lian ZX. Animal Models of Autoimmune Liver Diseases: a Comprehensive Review. Clin Rev Allergy Immunol 2020; 58:252-271. [PMID: 32076943 DOI: 10.1007/s12016-020-08778-6] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Autoimmune liver diseases (AILDs) are potentially life-threatening chronic liver diseases which include autoimmune hepatitis, primary biliary cholangitis, primary sclerosing cholangitis, and recently characterized IgG4-related sclerosing cholangitis. They are caused by immune attack on hepatocytes or bile ducts, with different mechanisms and clinical manifestations. The etiologies of AILDs include a susceptible genetic background, environment insults, infections, and changes of commensal microbiota, but remain complicated. Understanding of the underlying mechanisms of AILDs is mandatory for early diagnosis and intervention, which is of great importance for better prognosis. Thus, animal models are developed to mimic the pathogenesis, find biomarkers for early diagnosis, and for therapeutic attempts of AILDs. However, no animal models can fully recapitulate features of certain AILD, especially the late stages of diseases. Certain limitations include different living condition, cell composition, and time frame of disease development and resolution. Moreover, there is no IgG4 in rodents which exists in human. Nevertheless, the understanding and therapy of AILDs have been greatly advanced by the development and mechanistic investigation of animal models. This review will provide a comprehensive overview of traditional and new animal models that recapitulate different features and etiologies of distinct AILDs.
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Affiliation(s)
- Shou-Pei Liu
- Department of General Surgery, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, 510180, Guangdong, China.,Chronic Disease Laboratory, Institutes for Life Sciences and School of Medicine, South China University of Technology, Guangzhou, 510006, China
| | - Zhen-Hua Bian
- Department of General Surgery, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, 510180, Guangdong, China.,Chronic Disease Laboratory, Institutes for Life Sciences and School of Medicine, South China University of Technology, Guangzhou, 510006, China.,School of Biology and Biological Engineering, South China University of Technology, Guangzhou, 510006, Guangdong, China
| | - Zhi-Bin Zhao
- Department of General Surgery, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, 510180, Guangdong, China.,Chronic Disease Laboratory, Institutes for Life Sciences and School of Medicine, South China University of Technology, Guangzhou, 510006, China
| | - Jinjun Wang
- College of Environmental Science and Engineering, Yangzhou University, Yangzhou, 225127, Jiangsu, China
| | - Weici Zhang
- Division of Rheumatology/Allergy and Clinical Immunology, University of California, Davis, CA, 95616, USA
| | - Patrick S C Leung
- Division of Rheumatology/Allergy and Clinical Immunology, University of California, Davis, CA, 95616, USA
| | - Liang Li
- Department of General Surgery, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, 510180, Guangdong, China. .,Chronic Disease Laboratory, Institutes for Life Sciences and School of Medicine, South China University of Technology, Guangzhou, 510006, China.
| | - Zhe-Xiong Lian
- Department of General Surgery, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, 510180, Guangdong, China. .,Chronic Disease Laboratory, Institutes for Life Sciences and School of Medicine, South China University of Technology, Guangzhou, 510006, China.
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Wang H, Feng X, Yan W, Tian D. Regulatory T Cells in Autoimmune Hepatitis: Unveiling Their Roles in Mouse Models and Patients. Front Immunol 2020; 11:575572. [PMID: 33117375 PMCID: PMC7575771 DOI: 10.3389/fimmu.2020.575572] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Accepted: 09/07/2020] [Indexed: 12/11/2022] Open
Abstract
Autoimmune hepatitis (AIH) is a severe and chronic liver disease, and its incidence has increased worldwide in recent years. Research into the pathogenesis of AIH remains limited largely owing to the lack of suitable mouse models. The concanavalin A (ConA) mouse model is a typical and well-established model used to investigate T cell-dependent liver injury. However, ConA-induced hepatitis is acute and usually disappears after 48 h; thus, it does not mimic the pathogenesis of AIH in the human body. Several studies have explored various AIH mouse models, but as yet there is no widely accepted and valid mouse model for AIH. Immunosuppression is the standard clinical therapy for AIH, but patient side effects and recurrence limit its use. Regulatory T cells (Tregs) play critical roles in the maintenance of immune homeostasis and in the prevention of autoimmune diseases, which may provide a potential therapeutic target for AIH therapy. However, the role of Tregs in AIH has not yet been clarified, partly because of difficulties in diagnosing AIH and in collecting patient samples. In this review, we discuss the studies related to Treg in various AIH mouse models and patients with AIH and provide some novel insights for this research area.
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Affiliation(s)
- Han Wang
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xinxia Feng
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wei Yan
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Dean Tian
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Yang D, Huang WY, Li YQ, Chen SY, Su SY, Gao Y, Meng XL, Wang P. Acute and subchronic toxicity studies of rhein in immature and d-galactose-induced aged mice and its potential hepatotoxicity mechanisms. Drug Chem Toxicol 2020; 45:1119-1130. [DOI: 10.1080/01480545.2020.1809670] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Affiliation(s)
- Dong Yang
- College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Wan-Yi Huang
- College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Yan-Qiao Li
- College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Shi-Yu Chen
- College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Si-Yu Su
- College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Yue Gao
- College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Xian-Li Meng
- College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Ping Wang
- College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
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Peng X, Pan X, Tan J, Li Y, Li M. Protective effect of interleukin-36 receptor antagonist on liver injury induced by concanavalin A in mice. IRANIAN JOURNAL OF BASIC MEDICAL SCIENCES 2020; 23:623-628. [PMID: 32742600 PMCID: PMC7374990 DOI: 10.22038/ijbms.2020.35614.8492] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Objective(s): Interleukin-36 receptor antagonist (IL-36Ra) is a new member of the IL-1 family that exhibits anti-inflammatory activity in a variety of inflammatory and immune diseases. Our purpose was to determine the effect of IL-36Ra on liver injury in a mouse hepatitis model induced by concanavalin A (ConA). Materials and Methods: Mice were treated with IL-36Ra DNA or pcDNA3.1 control plasmid using a hydrodynamic gene delivery approach. Results: Our data reveal that treatment with IL-36Ra decreased liver inflammation and serum level of aminotransferases. Furthermore, IL-36Ra reduced ConA-induced pro-inflammatory cytokines (interferon-γ, tumor necrosis factor-α, and IL-17A) production when compared to control plasmid. Conclusion: Our results demonstrated that IL-36Ra is a critical protector against ConA-induced liver injury.
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Affiliation(s)
- Xiao Peng
- Department of Immunology, Medical School of Ningbo University, Ningbo 315211, China
| | - Xiuhe Pan
- Department of Immunology, Medical School of Ningbo University, Ningbo 315211, China
| | - Jun Tan
- Department of Hepatology, HwaMei Hospital, University of Chinese Academy of Sciences, Ningbo 315010, China
| | - Yan Li
- Department of Immunology, Medical School of Ningbo University, Ningbo 315211, China
| | - Mingcai Li
- Department of Immunology, Medical School of Ningbo University, Ningbo 315211, China
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Guo J, Shirozu K, Akahoshi T, Mizuta Y, Murata M, Yamaura K. The farnesyltransferase inhibitor tipifarnib protects against autoimmune hepatitis induced by Concanavalin A. Int Immunopharmacol 2020; 83:106462. [PMID: 32251961 DOI: 10.1016/j.intimp.2020.106462] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Revised: 03/18/2020] [Accepted: 03/29/2020] [Indexed: 12/12/2022]
Abstract
No effective treatment has been established for autoimmune hepatitis (AIH), except for liver transplantation in the fatal stage. Little is known about the roles and mechanisms of farnesyltransferase inhibitors (FTIs) in treating AIH. Thus, we investigated the specific role of the FTI, tipifarnib, in a Concanavalin A (Con A)-induced model of hepatitis. The effects of tipifarnib (10 mg/kg, intraperitoneal injection) were studied in Con A (20 mg/kg, intravenous injection)-challenged mice by histological, biochemical, and immunological analyses. Tipifarnib-treated mice were compared to phosphate-buffered saline (PBS)-treated mice. Con A caused liver injury characterized by increased plasma alanine aminotransferase (ALT) levels and marked histological changes. The increased serum ALT, interleukin-6, or interferon-γ (IFN-γ) levels were observed at 2 or 8 h; tumor necrosis factor-α levels at 2 h post-Con A administration decreased significantly in the tipifarnib group. Tipifarnib also suppressed Con A-induced activation of CD4+ cells (but not CD8+ T cells) in the liver and spleen, and also reversed the Con A-induced decrease of natural killer T (NKT) cells in the liver. Tipifarnib significantly inhibited IFN-γ production and STAT1 phosphorylation from CD4+ T cells (but not CD8+ T and NKT cells) in the liver at 2 h post-Con A administration. Tipifarnib significantly inhibited IFN-γ production by splenic CD4+ T cells at 48 h post-Con A injection in vitro. Tipifarnib also inhibited the expression of farnesylated proteins induced by Con A administration. In conclusion, tipifarnib inhibited IFN-γ derived from Con A-induced CD4+ T cell activation due to downregulated STAT1 phosphorylation, suggesting that Tipifarnib can protect against AIH.
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Affiliation(s)
- Jie Guo
- Department of Disaster and Emergency Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Kazuhiro Shirozu
- Department of Anesthesia and Critical Care Medicine, Kyushu University Hospital, Fukuoka, Japan.
| | - Tomohiko Akahoshi
- Department of Disaster and Emergency Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yukie Mizuta
- Department of Disaster and Emergency Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Masaharu Murata
- Center for Advanced Medical Innovation, Kyushu University, Fukuoka, Japan
| | - Ken Yamaura
- Department of Anesthesia and Critical Care Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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Hepatic ILC2 activity is regulated by liver inflammation-induced cytokines and effector CD4 + T cells. Sci Rep 2020; 10:1071. [PMID: 31974518 PMCID: PMC6978388 DOI: 10.1038/s41598-020-57985-w] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2019] [Accepted: 01/07/2020] [Indexed: 01/23/2023] Open
Abstract
In immune-mediated hepatitis, type 2 innate lymphoid cells (ILC2) as well as effector CD4+ T cells have been shown to drive disease pathology. However, less is known about mechanisms involved in the regulation of ILC2 function during liver inflammation. We showed that in homeostasis, hepatic ILC2 constituted a very small population with a naive, inactive phenotype. During immune-mediated hepatitis, the cytokines IL-33 and IFNγ were expressed in liver tissue. IL-33 induced strong activation and expression of type 2 cytokines as well as IL-6 by hepatic ILC2 while IFNγ suppressed cytokine production. Interestingly, this inhibitory effect was overcome by IL-33. The phenotype of activated hepatic ILC2 were stable since they did not show functional plasticity in response to liver inflammation-induced cytokines. Moreover, hepatic ILC2 induced a Th2 phenotype in activated CD4+ T cells, which increased ILC2-derived cytokine expression via IL-2. In contrast, Th1 cells inhibited survival of ILC2 by production of IFNγ. Thus, hepatic ILC2 function is regulated by IL-33, IL-2, and IFNγ. While IL-33 and IL-2 support hepatic ILC2 activation, their inflammatory activity in immune-mediated hepatitis might be limited by infiltrating IFNγ-expressing Th1 cells.
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Nabekura T, Riggan L, Hildreth AD, O’Sullivan TE, Shibuya A. Type 1 Innate Lymphoid Cells Protect Mice from Acute Liver Injury via Interferon-γ Secretion for Upregulating Bcl-xL Expression in Hepatocytes. Immunity 2020; 52:96-108.e9. [PMID: 31810881 PMCID: PMC8108607 DOI: 10.1016/j.immuni.2019.11.004] [Citation(s) in RCA: 70] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2019] [Revised: 10/01/2019] [Accepted: 11/07/2019] [Indexed: 01/27/2023]
Abstract
Although type 1 innate lymphoid cells (ILC1s) have been originally found as liver-resident ILCs, their pathophysiological role in the liver remains poorly investigated. Here, we demonstrated that carbon tetrachloride (CCl4) injection into mice activated ILC1s, but not natural killer (NK) cells, in the liver. Activated ILC1s produced interferon-γ (IFN-γ) and protected mice from CCl4-induced acute liver injury. IFN-γ released from activated ILC1s promoted the survival of hepatocytes through upregulation of Bcl-xL. An activating NK receptor, DNAM-1, was required for the optimal activation and IFN-γ production of liver ILC1s. Extracellular adenosine triphosphate accelerated interleukin-12-driven IFN-γ production by liver ILC1s. These findings suggest that ILC1s are critical for tissue protection during acute liver injury.
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Affiliation(s)
- Tsukasa Nabekura
- Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.,Department of Immunology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.,R&D Center for Innovative Drug Discovery, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan
| | - Luke Riggan
- Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Andrew D. Hildreth
- Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Timothy E. O’Sullivan
- Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.,Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Akira Shibuya
- Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan; Department of Immunology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan; R&D Center for Innovative Drug Discovery, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
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Wang H, Yan W, Feng Z, Gao Y, Zhang L, Feng X, Tian D. Plasma proteomic analysis of autoimmune hepatitis in an improved AIH mouse model. J Transl Med 2020; 18:3. [PMID: 31906950 PMCID: PMC6943959 DOI: 10.1186/s12967-019-02180-3] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2019] [Accepted: 12/13/2019] [Indexed: 12/28/2022] Open
Abstract
Background The prevalence of autoimmune hepatitis (AIH) is increasing, and its early clinical diagnosis is difficult. The pathogenesis of AIH remains unclear, and AIH-related studies are largely limited because of lack of suitable mouse models. Methods To obtain a good tool for research on AIH, we first established an improved immune-mediated mouse model that can mimic the pathological process of AIH as in the human body, through repeated injections of human cytochrome P450 2D6 (CYP2D6) plasmid. Next, a proteomic analysis based on isobaric tag (IBT) technology was performed to detect the differentially expressed proteins (DEPs), and related biological functions and pathways in the plasma of AIH and normal mice. Finally, we performed enzyme-linked immunosorbent assay (ELISA) to further confirm the most abundant DEP in the plasma of patients with AIH. Results Autoantibodies and the characteristic pathology of AIH were observed in our mouse model. Inflammatory infiltration also increased in the livers of AIH mice over time and plateaued by day 42 post the first injection. Chronic hepatitis was most severe on day 35 with the development of fibrosis as well, and the plasma of AIH mice were collected for proteomic analysis. A total of 176 DEPs were found in this experiment, of which 148 DEPs were up-regulated and 28 DEPs were down-regulated. Thirty significant Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways (P < 0.05) were detected. Arginine biosynthesis was found to be the most significant pathway involved in the AIH process. During the Gene Ontology (GO) analysis, most DEPs were found to be involved in the binding, cellular, and metabolic processes. Using ELISA, the most overexpressed DEP, serum amyloid A 1 (SAA1), was confirmed to be increased specifically in the plasma of patients with AIH compared to other chronic hepatitis. Different plasma levels of SAA1 were also found related to different grades of inflammation and stages of fibrosis in the liver of patients with AIH. Conclusions Our study is the first to describe the proteomics analysis of a true sense of AIH mouse model, which is beneficial for a better understanding of AIH pathogenesis and identifying potential biomarkers for its clinical diagnosis.
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Affiliation(s)
- Han Wang
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue 1095, Wuhan, 430030, People's Republic of China
| | - Wei Yan
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue 1095, Wuhan, 430030, People's Republic of China
| | - Zuohua Feng
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China
| | - Yuan Gao
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China
| | - Liu Zhang
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue 1095, Wuhan, 430030, People's Republic of China
| | - Xinxia Feng
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue 1095, Wuhan, 430030, People's Republic of China.
| | - Dean Tian
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue 1095, Wuhan, 430030, People's Republic of China.
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Tan K, Xie X, Shi W, Miao L, Dong X, Yang W, Shao C, Zhao H, Wang Y, Wang G, Hou F, Hong Y. Deficiency of canonical Wnt/β-catenin signalling in hepatic dendritic cells triggers autoimmune hepatitis. Liver Int 2020; 40:131-140. [PMID: 31505100 DOI: 10.1111/liv.14246] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2019] [Revised: 08/21/2019] [Accepted: 08/27/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease manifested with the aberrant activation of hepatic dendritic cells (HDCs) and the subsequent breakdown of immune homeostasis. As an important player, HDC maintains immunological balance between tolerance to self-antigens versus destruction against pathogens in liver. However, the intracellular signalling networks that program HDC remain unclear. We have now found the role of canonical Wnt/β-catenin signalling in HDCs. METHODS Liver sections from AIH patients and healthy subjects were stained for the markers of Wnt/β-catenin signalling. Concanavalin A (ConA) and HDC/Hepa1-6 vaccine-induced AIH mouse models were examined for liver injury, inflammation and immune cell functions by serum biochemistry, histology, quantitative reverse transcription polymerase chain reaction (qRT-PCR), enzyme-linked immunosorbent assay (ELISA) and flow cytometry analysis. Wnt/β-catenin signalling expression was measured using immunoblot and qRT-PCR. RESULTS Canonical Wnt/β-catenin signalling in HDC is deficient in AIH patients and a mouse model, which coincides with the immunogenic function of HDCs. Furthermore, Wnt ligand engagement reactivates Wnt/β-catenin signalling and recovers the immunoregulatory phenotype of HDCs, in turn alleviating the severity of AIH. Likewise, pharmacologic activation of Wnt/β-catenin signalling attenuates AIH progression. CONCLUSIONS We report here that the constitutively active canonical Wnt/β-catenin signalling confers HDCs tolerogenicity under steady-state conditions. Deficiency of this pathway gives rise to T cell-mediated immune response and incidence of AIH. It may act as a new pathogenesis and treatment target for AIH.
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Affiliation(s)
- Kangan Tan
- Infectious Diseases Department, Peking University First Hospital, Beijing, China
| | - Xuehai Xie
- General Surgery Department, Peking University First Hospital, Beijing, China
| | - Wanwan Shi
- Infectious Diseases Department, Peking University First Hospital, Beijing, China
| | - Liang Miao
- Qinhuangdao Third Hospital, Hebei, China
| | - Xiaoqin Dong
- Infectious Diseases Department, Peking University First Hospital, Beijing, China
| | - Wanna Yang
- Infectious Diseases Department, Peking University First Hospital, Beijing, China
| | - Chen Shao
- Pathology Department, Capital Medical University Youan Hospital, Beijing, China
| | - Hong Zhao
- Infectious Diseases Department, Peking University First Hospital, Beijing, China
| | - Yan Wang
- Infectious Diseases Department, Peking University First Hospital, Beijing, China
| | - Guiqiang Wang
- Infectious Diseases Department, Peking University First Hospital, Beijing, China
| | - Fengqin Hou
- Infectious Diseases Department, Peking University First Hospital, Beijing, China
| | - Yuan Hong
- Infectious Diseases Department, Peking University First Hospital, Beijing, China
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