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Li S, Zhang J, Wei W, Zhang Z, Huang W, Xia L. The important role of myeloid-derived suppressor cells: From hepatitis to liver cancer. Biochim Biophys Acta Rev Cancer 2025; 1880:189329. [PMID: 40262654 DOI: 10.1016/j.bbcan.2025.189329] [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: 09/26/2024] [Revised: 04/15/2025] [Accepted: 04/15/2025] [Indexed: 04/24/2025]
Abstract
Liver homeostasis is coordinated by crosstalk between resident and infiltrating inflammatory cells. Liver disease creates a dynamic inflammatory microenvironment characterized by aberrant metabolism and continuous hepatic regeneration, making it an important risk factor for hepatocellular carcinoma (HCC) as well as liver failure. Recent studies have revealed a critical heterogeneous population of myeloid-derived suppressor cells (MDSCs), which influence liver disease progression and malignancy by dynamically regulating the immune microenvironment. MDSCs play an important role in preventing excessive immune responses in the liver. However, MDSCs are also associated with the promotion of liver injury and liver cancer progression. The plasticity of MDSCs in liver disease is a unique challenge for therapeutic intervention strategies and requires a deeper understanding of the underlying mechanisms. Here, we review the role of MDSCs in the establishment and progression of liver disease and highlight the evidence for MDSCs as a priority target for current and future therapeutic strategies. We explore the fate of MDSCs from hepatitis to liver cancer, providing recent insights into potential targets for clinical intervention.
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Affiliation(s)
- Siwen Li
- Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Jiaqian Zhang
- Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Wang Wei
- Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Zhicheng Zhang
- Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China.
| | - Wenjie Huang
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Clinical Medicine Research Center for Hepatic Surgery of Hubei Province, Key Laboratory of Organ Transplantation, Ministry of Education and Ministry of Public Health, Wuhan, Hubei 430030, China.
| | - Limin Xia
- Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China.
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2
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Li D, Chen J, Lin B, Guo Y, Pan J, Yu C, Wan X. Celastrol pretreatment attenuates concanavalin A-induced hepatitis in mice by suppressing interleukin-6/STAT3-interleukin-17 signaling. J Gastroenterol Hepatol 2023; 38:821-829. [PMID: 36967570 DOI: 10.1111/jgh.16183] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 03/07/2023] [Accepted: 03/15/2023] [Indexed: 05/12/2023]
Abstract
BACKGROUND AND AIM Celastrol is extracted from Tripterygium wilfordii Hook F. It has been reported to have protective effects against various liver diseases and immune regulation of autoimmune diseases. However, little is known about whether celastrol protects against immune-mediated hepatitis. This study aimed to investigate the effect of celastrol on liver injury induced by concanavalin A (ConA) and the potential mechanisms. METHODS Intravenous administration of ConA was applied to induce acute liver injury in mice with or without pretreatment of celastrol. The effects of celastrol on ConA-induced liver injury were further demonstrated by biochemical and histopathological assessments, immunoblotting, and flow cytometry analysis. RESULTS Both biochemical and histopathological observations showed that pretreatment of celastrol significantly ameliorated liver injury induced by ConA. Moreover, the hepatocyte apoptosis and inflammatory responses induced by ConA were also improved in celastrol-pretreated mice. Further studies revealed that these improvements were characterized as the celastrol-mediated suppression of total interleukin (IL)-17 from liver mononuclear cells in ConA-treated mice. Flow cytometry analysis suggested that celastrol specifically decreased IL-17 production by CD4+ T cells but not by CD8+ T cells. Fundamentally, pretreatment with celastrol inhibited both the IL-6 produced by F4/80+ macrophages and the IL-6 receptor on Th17 cells in the liver, which further led to the downregulated activation of STAT3, thus accounting for blocked Th17 signaling. CONCLUSIONS Celastrol may exhibit immune regulatory effects by regulating IL-6/STAT3-IL-17 signaling in ConA-induced hepatitis, which suggested new potentials for celastrol to be applied in treating immune-mediated liver diseases.
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Affiliation(s)
- Dingwu Li
- Department of Gastroenterology, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, China
| | - Jianing Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, China
| | - Bingru Lin
- Department of Gastroenterology, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, China
| | - Yanjun Guo
- Department of Gastroenterology, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, China
| | - Jiaqi Pan
- Department of Gastroenterology, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, China
| | - Chaohui Yu
- Department of Gastroenterology, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, China
| | - Xingyong Wan
- Department of Gastroenterology, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, China
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Ghobadinezhad F, Ebrahimi N, Mozaffari F, Moradi N, Beiranvand S, Pournazari M, Rezaei-Tazangi F, Khorram R, Afshinpour M, Robino RA, Aref AR, Ferreira LMR. The emerging role of regulatory cell-based therapy in autoimmune disease. Front Immunol 2022; 13:1075813. [PMID: 36591309 PMCID: PMC9795194 DOI: 10.3389/fimmu.2022.1075813] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Accepted: 11/28/2022] [Indexed: 12/23/2022] Open
Abstract
Autoimmune disease, caused by unwanted immune responses to self-antigens, affects millions of people each year and poses a great social and economic burden to individuals and communities. In the course of autoimmune disorders, including rheumatoid arthritis, systemic lupus erythematosus, type 1 diabetes mellitus, and multiple sclerosis, disturbances in the balance between the immune response against harmful agents and tolerance towards self-antigens lead to an immune response against self-tissues. In recent years, various regulatory immune cells have been identified. Disruptions in the quality, quantity, and function of these cells have been implicated in autoimmune disease development. Therefore, targeting or engineering these cells is a promising therapeutic for different autoimmune diseases. Regulatory T cells, regulatory B cells, regulatory dendritic cells, myeloid suppressor cells, and some subsets of innate lymphoid cells are arising as important players among this class of cells. Here, we review the roles of each suppressive cell type in the immune system during homeostasis and in the development of autoimmunity. Moreover, we discuss the current and future therapeutic potential of each one of these cell types for autoimmune diseases.
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Affiliation(s)
- Farbod Ghobadinezhad
- Student Research Committee, Kermanshah University of Medical Sciences, Kermanshah, Iran,Universal Scientific Education and Research Network (USERN) Office, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Nasim Ebrahimi
- Division of Genetics, Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran
| | - Fatemeh Mozaffari
- Department of Nutrition, School of Medicine, Zabol University of Medical Sciences, Zabol, Iran
| | - Neda Moradi
- Division of Biotechnology, Department of Cell and Molecular Biology and Microbiology, Nourdanesh Institute of Higher Education, University of Meymeh, Isfahan, Iran
| | - Sheida Beiranvand
- Department of Biology, Faculty of Basic Sciences, Islamic Azad University, Shahrekord, Iran
| | - Mehran Pournazari
- Clinical Research Development Center, Imam Reza Hospital, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Fatemeh Rezaei-Tazangi
- Department of Anatomy, School of Medicine, Fasa University of Medical Sciences, Fasa, Iran
| | - Roya Khorram
- Bone and Joint Diseases Research Center, Department of Orthopedic Surgery, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Maral Afshinpour
- Department of Chemistry and Biochemistry, South Dakota State University, Brookings, SD, United States
| | - Rob A. Robino
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, United States,Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC, United States,Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, United States
| | - Amir Reza Aref
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, United States,Xsphera Biosciences, Boston, MA, United States,*Correspondence: Leonardo M. R. Ferreira, ; Amir Reza Aref,
| | - Leonardo M. R. Ferreira
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, United States,Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC, United States,Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, United States,*Correspondence: Leonardo M. R. Ferreira, ; Amir Reza Aref,
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Monocytic myeloid-derived suppressive cells mitigate over-adipogenesis of bone marrow microenvironment in aplastic anemia by inhibiting CD8 + T cells. Cell Death Dis 2022; 13:620. [PMID: 35851002 PMCID: PMC9293984 DOI: 10.1038/s41419-022-05080-5] [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: 04/01/2022] [Revised: 07/04/2022] [Accepted: 07/06/2022] [Indexed: 01/21/2023]
Abstract
Aplastic anemia (AA) is a blood disorder resulted from over-activated T-cell related hematopoietic failure, with the characterization of hypocellularity and enhanced adipogenic differentiation of mesenchymal stroma cells (MSCs) in bone marrow (BM). However, little is known about the relationship between immune imbalance and polarized adipogenic abnormity of BM microenvironment in this disease entity. In the present study, we differentiated BM-MSCs into osteoblastic or adipogenic lineages to mimic the osteo-adipogenic differentiation. Activated CD8+ T cells and interferon-γ (IFN-γ) were found to stimulate adipogenesis of BM-MSCs either in vitro or in vivo of AA mouse model. Interestingly, myeloid-derived suppressive cells (MDSCs), one of the immune-regulating populations, were decreased within BM of AA mice. We found that it was not CD11b+Ly6G+Ly6C- granulocytic-MDSCs (gMDSCs) but CD11b+Ly6G-Ly6C+ monocytic-MDSCs (mMDSCs) inhibiting both T cell proliferation and IFN-γ production via inducible nitric oxide synthetase (iNOS) pathway. Single-cell RNA-sequencing (scRNA-seq) of AA- and mMDSCs-treated murine BM cells revealed that mMDSCs transfusion could reconstitute BM hematopoietic progenitors by inhibiting T cells population and signature cytokines and decreasing immature Adipo-Cxcl12-abundant reticular cells within BM. Multi-injection of mMDSCs into AA mice reduced intra-BM T cells infiltration and suppressed BM adipogenesis, which subsequently restored the intra-BM immune balance and eventually prevented pancytopenia and hypo-hematopoiesis. In conclusion, adoptive transfusion of mMDSCs might be a novel immune-regulating strategy to treat AA, accounting for not only restoring the intra-BM immune balance but also improving stroma's multi-differentiating microenvironment.
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5
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Liver ischaemia-reperfusion injury: a new understanding of the role of innate immunity. Nat Rev Gastroenterol Hepatol 2022; 19:239-256. [PMID: 34837066 DOI: 10.1038/s41575-021-00549-8] [Citation(s) in RCA: 188] [Impact Index Per Article: 62.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/29/2021] [Indexed: 02/08/2023]
Abstract
Liver ischaemia-reperfusion injury (LIRI), a local sterile inflammatory response driven by innate immunity, is one of the primary causes of early organ dysfunction and failure after liver transplantation. Cellular damage resulting from LIRI is an important risk factor not only for graft dysfunction but also for acute and even chronic rejection and exacerbates the shortage of donor organs for life-saving liver transplantation. Hepatocytes, liver sinusoidal endothelial cells and Kupffer cells, along with extrahepatic monocyte-derived macrophages, neutrophils and platelets, are all involved in LIRI. However, the mechanisms underlying the responses of these cells in the acute phase of LIRI and how these responses are orchestrated to control and resolve inflammation and achieve homeostatic tissue repair are not well understood. Technological advances allow the tracking of cells to better appreciate the role of hepatic macrophages and platelets (such as their origin and immunomodulatory and tissue-remodelling functions) and hepatic neutrophils (such as their selective recruitment, anti-inflammatory and tissue-repairing functions, and formation of extracellular traps and reverse migration) in LIRI. In this Review, we summarize the role of macrophages, platelets and neutrophils in LIRI, highlight unanswered questions, and discuss prospects for innovative therapeutic regimens against LIRI in transplant recipients.
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6
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Li B, Lian M, Li Y, Qian Q, Zhang J, Liu Q, Tang R, Ma X. Myeloid-Derived Suppressive Cells Deficient in Liver X Receptor α Protected From Autoimmune Hepatitis. Front Immunol 2021; 12:732102. [PMID: 34512667 PMCID: PMC8427166 DOI: 10.3389/fimmu.2021.732102] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Accepted: 08/05/2021] [Indexed: 11/13/2022] Open
Abstract
Myeloid-derived suppressor cells (MDSCs) emerge as a promising candidate for the immunotherapy of autoimmune hepatitis (AIH). However, targets for modulating MDSC in AIH are still being searched. Liver X receptors (LXRs) are important nuclear receptors linking lipid metabolism and immune responses. Despite the extensive studies of LXR in myeloid compartment, its role in MDSCs is currently less understood. Herein, expression of LXRα was found to be upregulated in AIH patients and colocalized with hepatic MDSCs. In ConA-induced hepatitis, deletion of LXRα led to increased expansion of MDSCs in the liver and alleviated the hepatic injury. MDSCs in LXRα-/- mice exhibited enhanced proliferation and survival comparing with WT mice. T-cell proliferation assay and adoptive cell transfer experiment validated the potent immunoregulatory role of MDSCs in vitro and in vivo. Mechanistically, MDSCs from LXRα-/- mice possessed significantly lower expression of interferon regulatory factor 8 (IRF-8), a key negative regulator of MDSC differentiation. Transcriptional activation of IRF-8 by LXRα was further demonstrated. Conclusion We reported that abrogation of LXRα facilitated the expansion of MDSCs via downregulating IRF-8, and thereby ameliorated hepatic immune injury profoundly. Our work highlights the therapeutic potential of targeting LXRα in AIH.
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Affiliation(s)
| | | | | | | | | | | | | | - Xiong Ma
- *Correspondence: Xiong Ma, ; Ruqi Tang,
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7
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Zhao J, Chu F, Xu H, Guo M, Shan S, Zheng W, Tao Y, Zhou Y, Hu Y, Chen C, Ren T, Xu L. C/EBPα/miR-7 Controls CD4 + T-Cell Activation and Function and Orchestrates Experimental Autoimmune Hepatitis in Mice. Hepatology 2021; 74:379-396. [PMID: 33125780 DOI: 10.1002/hep.31607] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2020] [Revised: 09/01/2020] [Accepted: 09/29/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIMS Increasing evidence in recent years has suggested that microRNA-7 (miR-7) is an important gene implicated in the development of various diseases including HCC. However, the role of miR-7 in autoimmune hepatitis (AIH) is unknown. APPROACH AND RESULTS Herein, we showed that miR-7 deficiency led to exacerbated pathology in Concanavalin-A-induced murine acute autoimmune liver injury (ALI) model, accompanied by hyperactivation state of CD4+ T cells. Depletion of CD4+ T cells reduced the effect of miR-7 deficiency on the pathology of ALI. Interestingly, miR-7 deficiency elevated CD4+ T-cell activation, proliferation, and cytokine production in vitro. Adoptive cell transfer experiments showed that miR-7def CD4+ T cells could exacerbate the pathology of ALI. Further analysis showed that miR-7 expression was up-regulated in activated CD4+ T cells. Importantly, the transcription of pre-miR-7b, a major resource of mature miR-7 in CD4+ T cells, was dominantly dependent on transcription factor CCAAT enhancer binding protein alpha (C/EBPα), which binds to the core promoter region of the miR-7b gene. Global gene analysis showed that mitogen-activated protein kinase 4 (MAPK4) is a target of miR-7 in CD4+ T cells. Finally, the loss of MAPK4 could ameliorate the activation state of CD4+ T cells with or without miR-7 deficiency. Our studies document the important role of miR-7 in the setting of AIH induced by Concanavalin-A. Specifically, we provide evidence that the C/EBPα/miR-7 axis negatively controls CD4+ T-cell activation and function through MAPK4, thereby orchestrating experimental AIH in mice. CONCLUSIONS This study expands on the important role of miR-7 in liver-related diseases and reveals the value of the C/EBPα/miR-7 axis in CD4+ T-cell biological function for the pathogenesis of immune-mediated liver diseases.
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Affiliation(s)
- Juanjuan Zhao
- Special Key Laboratory of Gene Detection & Therapy of Guizhou Province, Zunyi Medical University, Zunyi, China.,Department of Immunology, Zunyi Medical University, Zunyi, China
| | - Fengyun Chu
- Special Key Laboratory of Gene Detection & Therapy of Guizhou Province, Zunyi Medical University, Zunyi, China.,Department of Immunology, Zunyi Medical University, Zunyi, China
| | - Hualin Xu
- Special Key Laboratory of Gene Detection & Therapy of Guizhou Province, Zunyi Medical University, Zunyi, China.,Department of Immunology, Zunyi Medical University, Zunyi, China
| | - Mengmeng Guo
- Special Key Laboratory of Gene Detection & Therapy of Guizhou Province, Zunyi Medical University, Zunyi, China.,Department of Immunology, Zunyi Medical University, Zunyi, China
| | - Shan Shan
- Department of Respiratory Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Wen Zheng
- Special Key Laboratory of Gene Detection & Therapy of Guizhou Province, Zunyi Medical University, Zunyi, China.,Department of Immunology, Zunyi Medical University, Zunyi, China
| | - Yijing Tao
- Special Key Laboratory of Gene Detection & Therapy of Guizhou Province, Zunyi Medical University, Zunyi, China.,Department of Immunology, Zunyi Medical University, Zunyi, China
| | - Ya Zhou
- Department of Medical physics, Zunyi Medical University, Zunyi, China
| | - Yan Hu
- Special Key Laboratory of Gene Detection & Therapy of Guizhou Province, Zunyi Medical University, Zunyi, China.,Department of Immunology, Zunyi Medical University, Zunyi, China
| | - Chao Chen
- Special Key Laboratory of Gene Detection & Therapy of Guizhou Province, Zunyi Medical University, Zunyi, China.,Department of Immunology, Zunyi Medical University, Zunyi, China
| | - Tao Ren
- Department of Respiratory Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Lin Xu
- Special Key Laboratory of Gene Detection & Therapy of Guizhou Province, Zunyi Medical University, Zunyi, China.,Department of Immunology, Zunyi Medical University, Zunyi, China
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Sehgal R, Kaur N, Ramakrishna G, Trehanpati N. Immune Surveillance by Myeloid-Derived Suppressor Cells in Liver Diseases. Dig Dis 2021; 40:301-312. [PMID: 34157708 DOI: 10.1159/000517459] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Accepted: 05/27/2021] [Indexed: 02/02/2023]
Abstract
BACKGROUND Myeloid-derived suppressor cells (MDSCs) are immunosuppressive in nature, originate in the bone marrow, and are mainly found in the blood, spleen, and liver. In fact, liver acts as an important organ for induction and accumulation of MDSCs, especially during infection, inflammation, and cancer. In humans and rodents, models of liver diseases revealed that MDSCs promote regeneration and drive the inflammatory processes, leading to hepatitis, fibrogenesis, and cirrhosis, ultimately resulting in hepatocellular carcinoma. SUMMARY This brief review is focused on the in-depth understanding of the key molecules involved in the expansion and regulation of MDSCs and their underlying immunosuppressive mechanisms in liver diseases. KEY MESSAGE Modulated MDSCs can be used for therapeutic purposes in inflammation, cancer, and sepsis.
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Affiliation(s)
- Rashi Sehgal
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India.,Amity Institute of Biotechnology (AIB), Amity University, Noida, India
| | - Navkiran Kaur
- Amity Institute of Biotechnology (AIB), Amity University, Noida, India
| | - Gayatri Ramakrishna
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Nirupma Trehanpati
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
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Wu Y, Min J, Ge C, Shu J, Tian D, Yuan Y, Zhou D. Interleukin 22 in Liver Injury, Inflammation and Cancer. Int J Biol Sci 2020; 16:2405-2413. [PMID: 32760208 PMCID: PMC7378634 DOI: 10.7150/ijbs.38925] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Accepted: 06/16/2020] [Indexed: 12/12/2022] Open
Abstract
Interleukin 22(IL-22), a member of the IL-10 cytokine family and is an emerging CD4+Th cytokine that plays an important role in anti-microbial defense, homeostasis and tissue repair. We are interested in IL-22 as it has the double function of suppressing or encouraging inflammation in various disease models including hepatic inflammation. As a survival factor for hepatocytes, IL-22 plays a protective role in many kinds of liver diseases, such as hepatitis, liver fibrosis, or hepatocellular carcinoma (HCC) by binding to the receptors IL-22R1 and IL-10R2. Overexpression of IL-22 reduces liver fibrosis by attenuating the activation of hepatic stellate cell (the main cell types involved in hepatic fibrosis), and down-regulating the levels of inflammatory cytokines. Administration of exogenous IL-22 increases the replication of hepatocytes by inhibiting cell apoptosis and promoting mitosis, ultimately plays a contributing role in liver regeneration. Furthermore, treatment with IL-22 activates hepatic signal transducer and activator of transcription 3 (STAT3), ameliorates hepatic oxidative stress and alcoholic fatty liver, effectively alleviate the liver damage caused by alcohol and toxicant. In conclusion, the hepatoprotective functions and liver regeneration promoting effect of IL-22 suggests the therapeutic potential of IL-22 in the treatment of human hepatic diseases.
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Affiliation(s)
- Ye Wu
- The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230022, China
| | - Jie Min
- The Second Hospital of Anhui Medical University, Hefei, Anhui, 230601, China
| | - Chang Ge
- The First Affiliated Hospital of University of Science and Technology of China, Hefei, Anhui, 230022, China
| | - Jinping Shu
- The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230022, China
| | - Di Tian
- The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230022, China
| | - Yuan Yuan
- The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230022, China
| | - Dian Zhou
- The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230022, China
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10
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Rohwer N, Jumpertz S, Erdem M, Egners A, Warzecha KT, Fragoulis A, Kühl AA, Kramann R, Neuss S, Rudolph I, Endermann T, Zasada C, Apostolova I, Gerling M, Kempa S, Hughes R, Lewis CE, Brenner W, Malinowski MB, Stockmann M, Schomburg L, Faller W, Sansom OJ, Tacke F, Morkel M, Cramer T. Non-canonical HIF-1 stabilization contributes to intestinal tumorigenesis. Oncogene 2019; 38:5670-5685. [PMID: 31043706 DOI: 10.1038/s41388-019-0816-4] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2018] [Revised: 03/25/2019] [Accepted: 03/26/2019] [Indexed: 01/20/2023]
Abstract
The hypoxia-inducible transcription factor HIF-1 is appreciated as a promising target for cancer therapy. However, conditional deletion of HIF-1 and HIF-1 target genes in cells of the tumor microenvironment can result in accelerated tumor growth, calling for a detailed characterization of the cellular context to fully comprehend HIF-1's role in tumorigenesis. We dissected cell type-specific functions of HIF-1 for intestinal tumorigenesis by lineage-restricted deletion of the Hif1a locus. Intestinal epithelial cell-specific Hif1a loss reduced activation of Wnt/β-catenin, tumor-specific metabolism and inflammation, significantly inhibiting tumor growth. Deletion of Hif1a in myeloid cells reduced the expression of fibroblast-activating factors in tumor-associated macrophages resulting in decreased abundance of tumor-associated fibroblasts (TAF) and robustly reduced tumor formation. Interestingly, hypoxia was detectable only sparsely and without spatial association with HIF-1α, arguing for an importance of hypoxia-independent, i.e., non-canonical, HIF-1 stabilization for intestinal tumorigenesis that has not been previously appreciated. This adds a further layer of complexity to the regulation of HIF-1 and suggests that hypoxia and HIF-1α stabilization can be uncoupled in cancer. Collectively, our data show that HIF-1 is a pivotal pro-tumorigenic factor for intestinal tumor formation, controlling key oncogenic programs in both the epithelial tumor compartment and the tumor microenvironment.
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Affiliation(s)
- Nadine Rohwer
- Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany
| | - Sandra Jumpertz
- Molecular Tumor Biology, Department of General Visceral and Transplantation Surgery, RWTH University Hospital, Pauwelsstraße 30, 52074, Aachen, Germany
| | - Merve Erdem
- Molecular Tumor Biology, Department of General Visceral and Transplantation Surgery, RWTH University Hospital, Pauwelsstraße 30, 52074, Aachen, Germany
| | - Antje Egners
- Molecular Tumor Biology, Department of General Visceral and Transplantation Surgery, RWTH University Hospital, Pauwelsstraße 30, 52074, Aachen, Germany
| | - Klaudia T Warzecha
- Medicine III, RWTH University Hospital, Pauwelsstraße 30, 52074, Aachen, Germany
| | - Athanassios Fragoulis
- Molecular Tumor Biology, Department of General Visceral and Transplantation Surgery, RWTH University Hospital, Pauwelsstraße 30, 52074, Aachen, Germany
| | - Anja A Kühl
- Research Center Immunosciences, Charité Universitätsmedizin Berlin, Hindenburgdamm 30, 12200, Berlin, Germany
| | - Rafael Kramann
- Medicine II, RWTH University Hospital, Pauwelsstraße 30, 52074, Aachen, Germany
| | - Sabine Neuss
- Pathology, RWTH University Hospital, Pauwelsstraße 30, 52074, Aachen, Germany
| | - Ines Rudolph
- Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany
| | - Tobias Endermann
- Experimental Endocrinology, Charité Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany
| | - Christin Zasada
- Max-Delbrück-Centrum, Robert-Rössle-Straße 10, 13125, Berlin, Germany
| | - Ivayla Apostolova
- Nuclear Medicine, Charité Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany
| | - Marco Gerling
- Biosciences and Nutrition, Karolinska Institutet, Alfred Nobels Allé 8, 17177, Stockholm, Sweden
| | - Stefan Kempa
- Max-Delbrück-Centrum, Robert-Rössle-Straße 10, 13125, Berlin, Germany
| | - Russell Hughes
- Oncology and Metabolism, University of Sheffield Medical School, Sheffield, S10 2RX, UK
| | - Claire E Lewis
- Oncology and Metabolism, University of Sheffield Medical School, Sheffield, S10 2RX, UK
| | - Winfried Brenner
- Nuclear Medicine, Charité Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany
| | - Maciej B Malinowski
- Surgery, Charité Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany
- Department for General Visceral, Vascular, and Pediatric Surgery, Saarland University Hospital, Homburg, Germany
| | - Martin Stockmann
- Surgery, Charité Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany
| | - Lutz Schomburg
- Experimental Endocrinology, Charité Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany
| | - William Faller
- Cancer Research UK Beatson Institute, Glasgow, G61 1BD, UK
- The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Owen J Sansom
- Cancer Research UK Beatson Institute, Glasgow, G61 1BD, UK
| | - Frank Tacke
- Medicine III, RWTH University Hospital, Pauwelsstraße 30, 52074, Aachen, Germany
| | - Markus Morkel
- Institute for Pathology, Charité Universitätsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Germany
| | - Thorsten Cramer
- Molecular Tumor Biology, Department of General Visceral and Transplantation Surgery, RWTH University Hospital, Pauwelsstraße 30, 52074, Aachen, Germany.
- NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands.
- ESCAM-European Surgery Center Aachen Maastricht, Aachen, Germany.
- ESCAM-European Surgery Center Aachen Maastricht, Maastricht, The Netherlands.
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11
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Phenotypic and Functional Diversities of Myeloid-Derived Suppressor Cells in Autoimmune Diseases. Mediators Inflamm 2018; 2018:4316584. [PMID: 30670926 PMCID: PMC6323474 DOI: 10.1155/2018/4316584] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2018] [Accepted: 12/09/2018] [Indexed: 02/07/2023] Open
Abstract
Myeloid-derived suppressor cells (MDSCs) are identified as a heterogeneous population of cells with the function to suppress innate as well as adaptive immune responses. The initial studies of MDSCs were primarily focused on the field of animal tumor models or cancer patients. In cancer, MDSCs play the deleterious role to inhibit tumor immunity and to promote tumor development. Over the past few years, an increasing number of studies have investigated the role of MDSCs in autoimmune diseases. The beneficial effects of MDSCs in autoimmunity have been reported by some studies, and thus, immunosuppressive MDSCs may be a novel therapeutic target in autoimmune diseases. There are some controversial findings as well. Many questions such as the activation, differentiation, and suppressive functions of MDSCs and their roles in autoimmune diseases remain unclear. In this review, we have discussed the current understanding of MDSCs in autoimmune diseases.
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12
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Xia G, Wu S, Wang X, Fu M. Inhibition of microRNA-155 attenuates concanavalin-A-induced autoimmune hepatitis by regulating Treg/Th17 cell differentiation. Can J Physiol Pharmacol 2018; 96:1293-1300. [PMID: 30290123 DOI: 10.1139/cjpp-2018-0467] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Autoimmune hepatitis (AIH) is a chronic progressive autoimmune disease characterized by hepatic inflammation. This study aimed to investigate the effect of antagomir-155 on concanavalin A (ConA)-induced AIH, and its possible mechanisms. According to the results, the expression of miR-155 was raised in liver tissues after 48 h exposure to ConA. Treatment with antagomir-155 attenuated ConA-induced liver injury in mice by reducing serum alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase levels. In addition, antagomir-155 significantly alleviated the differentiation of Treg/Th17 cells in the livers of AIH mice, and suppressed Th17-cells-mediated production of pro-inflammatory cytokines IL-17A, IL-23, but not Treg-cells-mediated production of anti-inflammatory cytokine IL-10. Finally, the beneficial effect of antagomir-155 on ConA-induced AIH was abolished by administration of recombinant IL-17A. Our data demonstrated that antagomir-155 treatment could prevent AIH via regulating the differentiation of Treg and Th17 cells, suggesting that microRNA-155 may be an intriguing therapeutic target of AIH.
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Affiliation(s)
- Guangtao Xia
- Department of Rheumatology and Immunology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, People’s Republic of China
| | - Sensen Wu
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, Shandong 250012, People’s Republic of China
| | - Xia Wang
- Department of Rheumatology and Immunology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, People’s Republic of China
| | - Min Fu
- Department of Rheumatology and Immunology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, People’s Republic of China
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13
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Lian M, Wang Q, Jiang X, Zhang J, Wei Y, Li Y, Li B, Chen W, Zhang H, Miao Q, Peng Y, Xiao X, Sheng L, Zhang W, Fang J, Tang R, Gershwin ME, Ma X. The Immunobiology of Receptor Activator for Nuclear Factor Kappa B Ligand and Myeloid-Derived Suppressor Cell Activation in Immunoglobulin G4-Related Sclerosing Cholangitis. Hepatology 2018; 68:1922-1936. [PMID: 29774578 DOI: 10.1002/hep.30095] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2017] [Revised: 03/08/2018] [Accepted: 04/22/2018] [Indexed: 12/24/2022]
Abstract
The primary function of myeloid-derived suppressor cells (MDSCs) is reflected in their immune modulatory role in several immune-mediated diseases. In immunoglobulin G4 (IgG4)-related disease (IgG4-RD), it has been hypothesized that there are selective regulatory defects that lead to a T helper 2 (Th2) bias immune response. Herein we have taken advantage of a large cohort of patients with IgG4-related sclerosing cholangitis (IgG4-SC), the most common extrapancreatic involvement of IgG4-RD, as well as controls consisting of primary sclerosing cholangitis, autoimmune hepatitis, and healthy volunteers, to study MDSCs. We report dramatically increased levels of receptor activator for nuclear factor kappa B ligand (RANKL) expression in serum and liver from patients with IgG4-SC compared to both liver-disease and healthy controls. Moreover, in IgG4-SC liver, RANKL-secreting cells specifically colocalized with cluster of differentiation 38-positive plasma cells and MDSCs, particularly monocytic MDSCs, and express the RANKL receptor in liver. Similarly, the frequency and number of peripheral blood MDSCs were significantly increased. Importantly, serum expression levels of RANKL were inversely correlated with the serum level of gamma-glutamyltransferase but significantly positively correlated with the frequency of MDSCs. Moreover, we confirmed that RANKL induced the expansion and activation of MDSCs through the RANKL/RANK/nuclear factor kappa B signal pathway. Of note, RANKL-treated MDSCs suppressed T-cell proliferation and induced Th2 differentiation. Conclusion: Our data suggest that plasma cell-derived RANKL induces the expansion and activation of MDSCs, which suppress T-cell proliferation and contribute to the Th2-type response characteristic of IgG4-SC.
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Affiliation(s)
- Min Lian
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health; State Key Laboratory for Oncogenes and Related Genes, Renji Hospital; School of Medicine, Shanghai Jiao Tong University; and Shanghai Institute of Digestive Disease, Shanghai, China
| | - Qixia Wang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health; State Key Laboratory for Oncogenes and Related Genes, Renji Hospital; School of Medicine, Shanghai Jiao Tong University; and Shanghai Institute of Digestive Disease, Shanghai, China
| | - Xiang Jiang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health; State Key Laboratory for Oncogenes and Related Genes, Renji Hospital; School of Medicine, Shanghai Jiao Tong University; and Shanghai Institute of Digestive Disease, Shanghai, China
| | - Jun Zhang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health; State Key Laboratory for Oncogenes and Related Genes, Renji Hospital; School of Medicine, Shanghai Jiao Tong University; and Shanghai Institute of Digestive Disease, Shanghai, China
| | - Yiran Wei
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health; State Key Laboratory for Oncogenes and Related Genes, Renji Hospital; School of Medicine, Shanghai Jiao Tong University; and Shanghai Institute of Digestive Disease, Shanghai, China
| | - Yanmei Li
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health; State Key Laboratory for Oncogenes and Related Genes, Renji Hospital; School of Medicine, Shanghai Jiao Tong University; and Shanghai Institute of Digestive Disease, Shanghai, China
| | - Bo Li
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health; State Key Laboratory for Oncogenes and Related Genes, Renji Hospital; School of Medicine, Shanghai Jiao Tong University; and Shanghai Institute of Digestive Disease, Shanghai, China
| | - Weihua Chen
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health; State Key Laboratory for Oncogenes and Related Genes, Renji Hospital; School of Medicine, Shanghai Jiao Tong University; and Shanghai Institute of Digestive Disease, Shanghai, China
| | - Haiyan Zhang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health; State Key Laboratory for Oncogenes and Related Genes, Renji Hospital; School of Medicine, Shanghai Jiao Tong University; and Shanghai Institute of Digestive Disease, Shanghai, China
| | - Qi Miao
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health; State Key Laboratory for Oncogenes and Related Genes, Renji Hospital; School of Medicine, Shanghai Jiao Tong University; and Shanghai Institute of Digestive Disease, Shanghai, China
| | - Yanshen Peng
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health; State Key Laboratory for Oncogenes and Related Genes, Renji Hospital; School of Medicine, Shanghai Jiao Tong University; and Shanghai Institute of Digestive Disease, Shanghai, China
| | - Xiao Xiao
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health; State Key Laboratory for Oncogenes and Related Genes, Renji Hospital; School of Medicine, Shanghai Jiao Tong University; and Shanghai Institute of Digestive Disease, Shanghai, China
| | - Li Sheng
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health; State Key Laboratory for Oncogenes and Related Genes, Renji Hospital; School of Medicine, Shanghai Jiao Tong University; and Shanghai Institute of Digestive Disease, Shanghai, China
| | - Weici Zhang
- Division of Rheumatology, Allergy and Clinical Immunology, Department of Internal Medicine, University of California at Davis, Davis, CA
| | - Jingyuan Fang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health; State Key Laboratory for Oncogenes and Related Genes, Renji Hospital; School of Medicine, Shanghai Jiao Tong University; and Shanghai Institute of Digestive Disease, Shanghai, China
| | - Ruqi Tang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health; State Key Laboratory for Oncogenes and Related Genes, Renji Hospital; School of Medicine, Shanghai Jiao Tong University; and Shanghai Institute of Digestive Disease, Shanghai, China
| | - M Eric Gershwin
- Division of Rheumatology, Allergy and Clinical Immunology, Department of Internal Medicine, University of California at Davis, Davis, CA
| | - Xiong Ma
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health; State Key Laboratory for Oncogenes and Related Genes, Renji Hospital; School of Medicine, Shanghai Jiao Tong University; and Shanghai Institute of Digestive Disease, Shanghai, China
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14
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Cai G, Sun K, Wang T, Zou H, Gu J, Yuan Y, Liu X, Liu Z, Bian J. Mechanism and effects of Zearalenone on mouse T lymphocytes activation in vitro. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2018; 162:208-217. [PMID: 29990733 DOI: 10.1016/j.ecoenv.2018.06.055] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/02/2018] [Revised: 06/16/2018] [Accepted: 06/19/2018] [Indexed: 06/08/2023]
Abstract
Zearalenone (ZEA) is particularly toxic to the female reproductive system. Nevertheless, the effect of ZEA on the immune system is still not fully understood. The following study investigates the effects and mechanism of ZEA on mouse T cell activation in vitro. Briefly, T lymphocytes were extracted from primary splenic lymphocyte in mice, activated by concanavalin A, and then were exposed to different concentrations of ZEA for a certain period of time. Flow cytometry was used to detect the expression of activating and co-stimulatory molecules, and the secretion of cytokines in T cells at various stages. The expression of initiation regulatory protein in T cell activation, nuclear factor protein and co-stimulatory molecule related PI3K-Akt-mTOR signaling pathway proteins were detected by western blot. Our data showed that ZEA exposure inhibits the activity of T cell, and inhibits the expression of different activation signals in T cell. Additionally, ZEA exposure reduces the expression of initiative regulatory protein, i.e. LAT, Lck, Zap-70 during the activation of T cells. Thus, the results showed that ZEA exposure inhibits the formation and transmission of activated signal in T cells, interferes with signal pathway of T cell activation nuclear factor NFAT and NFκB, and decreases the secretion of cytokines after activation. Moreover, ZEA exposure interferes with co-stimulatory molecule CD28 during T cell activation, and with the activity of the PI3K-Akt-mTOR signaling pathway downstream of CD28. To conclude, our results indicated that ZEA toxin interferes with the activation of mouse T lymphocytes by affecting TCR signal and co-stimulatory signal, thus playing an essential role in immune toxicity.
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Affiliation(s)
- Guodong Cai
- College of Veterinary Medicine, Yangzhou University, 12 Wenhui East Road, Yangzhou 225009, Jiangsu, China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, Jiangsu, China; Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education of China, Yangzhou University, Yangzhou 225009, Jiangsu, China
| | - Kai Sun
- College of Veterinary Medicine, Yangzhou University, 12 Wenhui East Road, Yangzhou 225009, Jiangsu, China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, Jiangsu, China
| | - Tao Wang
- College of Veterinary Medicine, Yangzhou University, 12 Wenhui East Road, Yangzhou 225009, Jiangsu, China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, Jiangsu, China
| | - Hui Zou
- College of Veterinary Medicine, Yangzhou University, 12 Wenhui East Road, Yangzhou 225009, Jiangsu, China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, Jiangsu, China
| | - Jianhong Gu
- College of Veterinary Medicine, Yangzhou University, 12 Wenhui East Road, Yangzhou 225009, Jiangsu, China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, Jiangsu, China
| | - Yan Yuan
- College of Veterinary Medicine, Yangzhou University, 12 Wenhui East Road, Yangzhou 225009, Jiangsu, China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, Jiangsu, China
| | - Xuezhong Liu
- College of Veterinary Medicine, Yangzhou University, 12 Wenhui East Road, Yangzhou 225009, Jiangsu, China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, Jiangsu, China
| | - Zongping Liu
- College of Veterinary Medicine, Yangzhou University, 12 Wenhui East Road, Yangzhou 225009, Jiangsu, China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, Jiangsu, China; Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education of China, Yangzhou University, Yangzhou 225009, Jiangsu, China
| | - Jianchun Bian
- College of Veterinary Medicine, Yangzhou University, 12 Wenhui East Road, Yangzhou 225009, Jiangsu, China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, Jiangsu, China; Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education of China, Yangzhou University, Yangzhou 225009, Jiangsu, China.
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15
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Ferretti AP, Bhargava R, Dahan S, Tsokos MG, Tsokos GC. Calcium/Calmodulin Kinase IV Controls the Function of Both T Cells and Kidney Resident Cells. Front Immunol 2018; 9:2113. [PMID: 30333818 PMCID: PMC6176098 DOI: 10.3389/fimmu.2018.02113] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2018] [Accepted: 08/28/2018] [Indexed: 12/12/2022] Open
Abstract
Calcium calmodulin kinase IV (CaMK4) regulates multiple processes that significantly contribute to the lupus-related pathology by controlling the production of IL-2 and IL-17 by T cells, the proliferation of mesangial cells, and the function and structure of podocytes. CaMK4 is also upregulated in podocytes from patients with focal segmental glomerulosclerosis (FSGS). In both immune and non-immune podocytopathies, CaMK4 disrupts the structure and function of podocytes. In lupus-prone mice, targeted delivery of a CaMK4 inhibitor to CD4+ T cells suppresses both autoimmunity and the development of nephritis. Targeted delivery though to podocytes averts the deposition of immune complexes without affecting autoimmunity in lupus-prone mice and averts pathology induced by adriamycin in normal mice. Therefore, targeted delivery of a CaMK4 inhibitor to podocytes holds high therapeutic promise for both immune (lupus nephritis) and non-immune (FSGS) podocytopathies.
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Affiliation(s)
- Andrew P Ferretti
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
| | - Rhea Bhargava
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
| | - Shani Dahan
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
| | - Maria G Tsokos
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
| | - George C Tsokos
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
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16
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Lv Y, Cui M, Lv Z, Lu J, Zhang X, Zhao Z, Wang Y, Gao L, Tsuji NM, Yan H. Expression and significance of peripheral myeloid-derived suppressor cells in chronic hepatitis B patients. Clin Res Hepatol Gastroenterol 2018; 42:462-469. [PMID: 29753730 DOI: 10.1016/j.clinre.2018.04.002] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2017] [Revised: 03/29/2018] [Accepted: 04/10/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND Myeloid-derived suppressor cells (MDSCs) exert their suppressive effects on multiple immune response and contribute to the development of many diseases. However, limited data is available on the involvement of MDSCs in human chronic HBV infection. OBJECTIVE To investigate whether the progression of chronic HBV infection was associated with imbalance of MDSCs. METHODS The percentages of MDSCs, regulatory T (Treg), Th1 and Tc1 cells in the peripheral blood from chronic hepatitis B (CHB) patients and healthy controls (HC) were determined by flow cytometry. Plasma levels of IL-10, TGF-β and IFN-γ were measured using enzyme-linked immunosorbent assay. The potential association of the frequencies of MDSCs with clinical parameters was assessed. RESULTS The percentages of MDSCs and Treg cells were significantly higher in CHB patients than those in HC. The percentages of MDSCs were negatively correlated with Th1 cells. Increased plasma IL-10 level and decreased IFN-γ level were found in CHB patients compared with HC. Moreover, the frequencies of MDSCs and plasma IL-10 levels were positively correlated with serum HBV DNA loads, as well as liver function impairment. CONCLUSION The expanded peripheral MDSCs may contribute to poor viral clearance and disease progression during chronic HBV infection.
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Affiliation(s)
- Y Lv
- Clinical Research Center, Shijiazhuang Fifth Hospital, 42, Tanan Road, Shijiazhuang, Hebei 050021, China
| | - M Cui
- Department of Liver and Digestive Disease, Shijiazhuang Fifth Hospital, Shijiazhuang, Hebei 050021, China
| | - Z Lv
- Graduate College of Hebei Medical University, Hebei Medical University, Shijiazhuang, Hebei 050017, China
| | - J Lu
- Clinical Research Center, Shijiazhuang Fifth Hospital, 42, Tanan Road, Shijiazhuang, Hebei 050021, China
| | - X Zhang
- Graduate College of Hebei Medical University, Hebei Medical University, Shijiazhuang, Hebei 050017, China
| | - Z Zhao
- Department of Liver and Digestive Disease, Shijiazhuang Fifth Hospital, Shijiazhuang, Hebei 050021, China
| | - Y Wang
- Department of Liver and Digestive Disease, Shijiazhuang Fifth Hospital, Shijiazhuang, Hebei 050021, China
| | - L Gao
- College of Life Science, Hebei Normal University, Shijiazhuang, Hebei 050024, China
| | - N M Tsuji
- Biomedical Research Institude, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki 305-8566, Japan
| | - H Yan
- Clinical Research Center, Shijiazhuang Fifth Hospital, 42, Tanan Road, Shijiazhuang, Hebei 050021, China.
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17
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Lian M, Selmi C, Gershwin ME, Ma X. Myeloid Cells and Chronic Liver Disease: a Comprehensive Review. Clin Rev Allergy Immunol 2018; 54:307-317. [PMID: 29313221 DOI: 10.1007/s12016-017-8664-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Myeloid cells play a major role in the sensitization to liver injury, particularly in chronic inflammatory liver diseases with a biliary or hepatocellular origin, and the interplay between myeloid cells and the liver may explain the increased incidence of hepatic osteodystrophy. The myeloid cell-liver axis involves several mature myeloid cells as well as immature or progenitor cells with the complexity of the liver immune microenvironment aggravating the mist of cell differentiation. The unique positioning of the liver at the junction of the peripheral and portal circulation systems underlines the interaction of myeloid cells and hepatic cells and leads to immune tolerance breakdown. We herein discuss the scenarios of different chronic liver diseases closely modulated by myeloid cells and illustrate the numerous potential targets, the understanding of which will ultimately steer the development of solid immunotherapeutic regimens. Ultimately, we are convinced that an adequate modulation of the liver microenvironment to modify the functional and quantitative characteristics of myeloid cells will be a successful approach to treating chronic liver diseases of different etiologies.
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Affiliation(s)
- Min Lian
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, 200001, China
| | - Carlo Selmi
- Division of Rheumatology and Clinical Immunology, Humanitas Research Hospital, Rozzano, Italy.,BIOMETRA Department, University of Milan, Milan, Italy
| | - M Eric Gershwin
- Division of Rheumatology, Department of Medicine, Allergy and Clinical Immunology, University of California at Davis, Davis, CA, USA
| | - Xiong Ma
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, 200001, China.
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18
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Li S, Wang N, Tan HY, Hong M, Yuen MF, Li H, Feng Y. Expansion of Granulocytic, Myeloid-Derived Suppressor Cells in Response to Ethanol-Induced Acute Liver Damage. Front Immunol 2018; 9:1524. [PMID: 30072984 PMCID: PMC6060237 DOI: 10.3389/fimmu.2018.01524] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2018] [Accepted: 06/20/2018] [Indexed: 02/06/2023] Open
Abstract
The dual role of ethanol in regulating both pro-inflammatory and anti-inflammatory response has recently been reported. Myeloid-derived suppressor cells (MDSCs) are one of the major components in the immune suppressive network in both innate and adaptive immune responses. In this study, we aim to define the role of a population expressing CD11b+Ly6GhighLy6Cint with immunosuppressive function in response to ethanol-induced acute liver damage. We find this increased granulocytic-MDSCs (G-MDSCs) population in the blood, spleen, and liver of mice treated with ethanol. Depletion of these cells increases serum alanine aminotransferase and aspartate aminotransferase levels, while G-MDSCs population adoptive transfer can ameliorate liver damage induced by ethanol, indicating the protective role in the early stage of alcoholic liver disease. The significant changes of T-cell profiles after G-MDSCs populations adoptive transfer and anti-Gr1 injection signify that both cytotoxic T and T helper cells might be the targeted cells of G-MDSCs. In the in vitro study, we find that myeloid precursors preferentially generate G-MDSCs and improve their suppressive capacity via chemokine interaction and YAP signaling when exposed to ethanol. Furthermore, IL-6 serves as an important indirect factor in mediating the expansion of G-MDSCs populations after acute ethanol exposure. Collectively, we show that expansion of G-MDSCs in response to ethanol consumption plays a protective role in acute alcoholic liver damage. Our study provides novel evidence of the immune response to acute ethanol consumption.
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Affiliation(s)
- Sha Li
- Li Ka Shing Faculty of Medicine, School of Chinese Medicine, The University of Hong Kong, Pokfulam, Hong Kong
| | - Ning Wang
- Li Ka Shing Faculty of Medicine, School of Chinese Medicine, The University of Hong Kong, Pokfulam, Hong Kong
| | - Hor-Yue Tan
- Li Ka Shing Faculty of Medicine, School of Chinese Medicine, The University of Hong Kong, Pokfulam, Hong Kong
| | - Ming Hong
- Li Ka Shing Faculty of Medicine, School of Chinese Medicine, The University of Hong Kong, Pokfulam, Hong Kong
| | - Man-Fung Yuen
- Division of Gastroenterology and Hepatology, Queen Mary Hospital, Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong
| | - Huabin Li
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University, Guangzhou, China
| | - Yibin Feng
- Li Ka Shing Faculty of Medicine, School of Chinese Medicine, The University of Hong Kong, Pokfulam, Hong Kong
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19
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Wen L, Gong P, Liang C, Shou D, Liu B, Chen Y, Bao C, Chen L, Liu X, Liang T, Gong W. Interplay between myeloid-derived suppressor cells (MDSCs) and Th17 cells: foe or friend? Oncotarget 2018; 7:35490-6. [PMID: 27007054 PMCID: PMC5085246 DOI: 10.18632/oncotarget.8204] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2015] [Accepted: 03/02/2016] [Indexed: 12/25/2022] Open
Abstract
Myeloid-derived suppressor cells (MDSCs) and Th17 cells were first discovered in the fields of cancer and autoimmunity, respectively. In recent years, their activities have been explored in other biological and pathological conditions, such as infective diseases and solid organ transplantation. However, the interplay between MDSCs and Th17 cells and the mechanism of their interaction remain obscure. This review summarized and analyzed the relationship between MDSCs and Th17 cells, both of which participate in tumor, autoimmune disease, infection and other conditions. In tumors, the increase in MDSCs at the tumor site is usually accompanied by the accumulation of Th17 cells. However, their relationship is inconsistent in different tumors. In arthritic mice or rheumatoid arthritis (RA) patients, an increase in MDSCs, which could ameliorate disease symptoms, causes decreased IL-17A gene expression and Th17 cells accumulation. Furthermore, we concluded that the interaction between MDSCs and Th17 cells is mainly mediated by cytokines. However, the mechanisms require further investigation. Determining the details of their interplay will provide a better understanding of immune networks and could lead to the development of immunotherapeutic strategies in the future.
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Affiliation(s)
- Liang Wen
- Department of Surgery, Second Affiliated Hospital of School of Medicine, Zhejiang University, Hangzhou City, People's Republic of China
| | - Ping Gong
- Department of Oncology, First Affiliated Hospital of Shihezi University School of Medicine, Shihezi City, People's Republic of China
| | - Chao Liang
- Department of Surgery, Second Affiliated Hospital of School of Medicine, Zhejiang University, Hangzhou City, People's Republic of China
| | - Dawei Shou
- Department of Surgery, Second Affiliated Hospital of School of Medicine, Zhejiang University, Hangzhou City, People's Republic of China
| | - Baoqing Liu
- Department of Surgery, Second Affiliated Hospital of School of Medicine, Zhejiang University, Hangzhou City, People's Republic of China
| | - Yiwen Chen
- Department of Surgery, Second Affiliated Hospital of School of Medicine, Zhejiang University, Hangzhou City, People's Republic of China
| | - Changqian Bao
- Department of Surgery, Second Affiliated Hospital of School of Medicine, Zhejiang University, Hangzhou City, People's Republic of China
| | - Li Chen
- Department of Surgery, Second Affiliated Hospital of School of Medicine, Zhejiang University, Hangzhou City, People's Republic of China
| | - Xiaowei Liu
- Division of Gastroenterology, Xiangya Second Hospital, Central South University, Hunan, People's Republic of China
| | - Tingbo Liang
- Department of Surgery, Second Affiliated Hospital of School of Medicine, Zhejiang University, Hangzhou City, People's Republic of China
| | - Weihua Gong
- Department of Surgery, Second Affiliated Hospital of School of Medicine, Zhejiang University, Hangzhou City, People's Republic of China
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20
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Dorhoi A, Du Plessis N. Monocytic Myeloid-Derived Suppressor Cells in Chronic Infections. Front Immunol 2018; 8:1895. [PMID: 29354120 PMCID: PMC5758551 DOI: 10.3389/fimmu.2017.01895] [Citation(s) in RCA: 115] [Impact Index Per Article: 16.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2017] [Accepted: 12/11/2017] [Indexed: 01/04/2023] Open
Abstract
Heterogeneous populations of myeloid regulatory cells (MRC), including monocytes, macrophages, dendritic cells, and neutrophils, are found in cancer and infectious diseases. The inflammatory environment in solid tumors as well as infectious foci with persistent pathogens promotes the development and recruitment of MRC. These cells help to resolve inflammation and establish host immune homeostasis by restricting T lymphocyte function, inducing regulatory T cells and releasing immune suppressive cytokines and enzyme products. Monocytic MRC, also termed monocytic myeloid-derived suppressor cells (M-MDSC), are bona fide phagocytes, capable of pathogen internalization and persistence, while exerting localized suppressive activity. Here, we summarize molecular pathways controlling M-MDSC genesis and functions in microbial-induced non-resolved inflammation and immunopathology. We focus on the roles of M-MDSC in infections, including opportunistic extracellular bacteria and fungi as well as persistent intracellular pathogens, such as mycobacteria and certain viruses. Better understanding of M-MDSC biology in chronic infections and their role in antimicrobial immunity, will advance development of novel, more effective and broad-range anti-infective therapies.
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Affiliation(s)
- Anca Dorhoi
- Institute of Immunology, Bundesforschungsinstitut für Tiergesundheit, Friedrich-Loeffler-Institut (FLI), Insel Riems, Germany.,Faculty of Mathematics and Natural Sciences, University of Greifswald, Greifswald, Germany.,Department of Immunology, Max Planck Institute for Infection Biology, Berlin, Germany
| | - Nelita Du Plessis
- Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, SAMRC Centre for Tuberculosis Research, DST and NRF Centre of Excellence for Biomedical TB Research, Stellenbosch University, Tygerberg, South Africa
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21
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Shen X, Peng Y, Li H. The Injury-Related Activation of Hedgehog Signaling Pathway Modulates the Repair-Associated Inflammation in Liver Fibrosis. Front Immunol 2017; 8:1450. [PMID: 29163520 PMCID: PMC5681491 DOI: 10.3389/fimmu.2017.01450] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2017] [Accepted: 10/17/2017] [Indexed: 12/13/2022] Open
Abstract
Liver fibrosis is a wound healing response initiated by inflammation responding for different iterative parenchymal damages caused by diverse etiologies. Immune cells, which exert their ability of either inducing injury or promoting repair, have been regarded as crucial participants in the fibrogenic response. A characteristic feature of the fibrotic microenvironment associated with chronic liver injury is aberrant activation of hedgehog (Hh) signaling pathway. Growing evidence from a number of different studies in vivo and in vitro has indicated that immune-mediated events involved in liver fibrogenesis are regulated by Hh signaling pathway. In this review, we emphasize the impacts of injury-activated Hh signaling on liver fibrogenesis through modulating repair-related inflammation and focus on the regulatory action of aberrant Hh signaling on repair-related inflammatory responses mediated by hepatic classical and non-classical immune cell populations in the progression of liver fibrosis. Moreover, we also assess the potentiality of Hh pathway inhibitors as good candidates for anti-fibrotic therapeutic agents because of their immune regulation actions for fibrogenic liver repair. The identification of immune-modulatory mechanisms of Hh signaling pathway underlying the fibrotic process of chronic liver diseases might provide a basis for Hh-centered therapeutic strategies for liver fibrosis.
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Affiliation(s)
- Xin Shen
- Department of Laboratory Medicine, Hubei University of Chinese Medicine, Wuhan, China
| | - Yu Peng
- Department of Information Engineering, Hubei University of Chinese Medicine, Wuhan, China
| | - Hanmin Li
- Hepatic Disease Institute, Hubei Provincial Hospital of Traditional Chinese Medicine, Affiliated Hospital of Hubei University of Chinese Medicine, Hubei Province Academy of Traditional Chinese Medicine, Wuhan, China
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22
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Bartneck M, Schlößer CT, Barz M, Zentel R, Trautwein C, Lammers T, Tacke F. Immunomodulatory Therapy of Inflammatory Liver Disease Using Selectin-Binding Glycopolymers. ACS NANO 2017; 11:9689-9700. [PMID: 28829572 DOI: 10.1021/acsnano.7b04630] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/07/2023]
Abstract
Immunotherapies have the potential to significantly advance treatment of inflammatory disease and cancer, which are in large part driven by immune cells. Selectins control the first step in immune cell adhesion and extravasation, thereby guiding leukocyte trafficking to tissue lesions. We analyzed four different highly specific selectin-binding glycopolymers, based on linear poly(2-hydroxypropyl)-methacrylamide (PHPMA) polymers. These glycopolymers contain either the tetrasaccharide sialyl-LewisX (SLeX) or the individual carbohydrates fucose, galactose, and sialic acids mimicking the complex SLeX binding motive. The glycopolymers strongly bind to primary human macrophages, without activating them, and also to primary human blood leukocytes, but poorly to fibroblasts and endothelial cells in vitro. After intravenous injection in mice, all glycopolymers accumulated in the liver without causing hepatotoxicity. The glycosylated binder most potently targeted resident hepatic macrophages (Kupffer cells) and protected mice from acute toxic liver injury in the two different experimental models, carbon tetrachloride (CCl4) or Concanavalin A (ConA)-based hepatitis. Its sulfated counterpart, on the other hand, induced a decrease in infiltrating and resident macrophages, increased T helper cells, and aggravated immune-mediated liver injury. We demonstrate that, in the context of selectin-binding glycopolymers, minor modifications strongly impact leukocyte influx and macrophage activation, thereby ameliorating or aggravating liver inflammation depending on the underlying immunopathology. The nonsulfated random glycopolymer is a promising candidate for the treatment of inflammatory disease. The modulation of hepatic immune cells by selectin-binding glycopolymers might breach the immunosuppressive hepatic microenvironment and could improve efficacy of immunotherapies for inflammatory disease and cancer.
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Affiliation(s)
| | | | - Matthias Barz
- Institute for Organic Chemistry, Johannes Gutenberg-University Mainz , 55122 Mainz, Germany
| | - Rudolf Zentel
- Institute for Organic Chemistry, Johannes Gutenberg-University Mainz , 55122 Mainz, Germany
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23
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Kuttkat N, Mohs A, Ohl K, Hooiveld G, Longerich T, Tenbrock K, Cubero FJ, Trautwein C. Hepatic overexpression of cAMP-responsive element modulator α induces a regulatory T-cell response in a murine model of chronic liver disease. Gut 2017; 66:908-919. [PMID: 27686093 PMCID: PMC5531221 DOI: 10.1136/gutjnl-2015-311119] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2015] [Accepted: 08/17/2016] [Indexed: 12/14/2022]
Abstract
OBJECTIVE Th17 cells are a subset of CD4+ T-helper cells characterised by interleukin 17 (IL-17) production, a cytokine that plays a crucial role in inflammation-associated diseases. The cyclic AMP-responsive element modulator-α (CREMα) is a central mediator of T-cell pathogenesis, which contributes to increased IL-17 expression in patients with autoimmune disorders. Since an increased Th17 response is associated with a poor prognosis in patients with chronic liver injury, we investigated the relevance of Th17 cells for chronic liver disease (CLD) and hepatocarcinogenesis. DESIGN Transgenic mice overexpressing CREMα were crossed with hepatocyte-specific Nemo knockout mice (NemoΔhepa) to generate NemoΔhepa/CREMαTg mice. The impact of CREMαTg on CLD progression was examined. Additionally, soft agar colony formation assays, in vitro studies, adoptive transfer of bone marrow-derived cells (BMDCs) and T cells, and gene arrays in T cells were performed. RESULTS 8-week-old NemoΔhepa/CREMαTg mice presented significantly decreased transaminase levels, concomitant with reduced numbers of CD11b+ dendritic cells and CD8+ T cells. CREMαTg overexpression in NemoΔhepa mice was associated with significantly reduced hepatic fibrogenesis and carcinogenesis at 52 weeks. Interestingly, hepatic stellate cell-derived retinoic acid induced a regulatory T-cell (Treg) phenotype in CREMαTg hepatic T cells. Moreover, simultaneous adoptive transfer of BMDCs and T cells from CREMαTg into NemoΔhepa mice ameliorated markers of liver injury and hepatitis. CONCLUSIONS Our results demonstrate that overexpression of CREMα in T cells changes the inflammatory milieu, attenuating initiation and progression of CLD. Unexpectedly, our study indicates that CREMα transgenic T cells shift chronic inflammation in NemoΔhepa livers towards a protective Treg response.
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Affiliation(s)
- Nadine Kuttkat
- Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Antje Mohs
- Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Kim Ohl
- Department of Pediatrics, University Hospital RWTH Aachen, Aachen, Germany
| | - Guido Hooiveld
- Institute for Nutrition, Metabolism & Genomics, Wageningen University & Research Centre, Wageningen, Netherlands
| | - Thomas Longerich
- Institute of Pathology, RWTH University Hospital Aachen, Aachen, Germany
| | - Klaus Tenbrock
- Department of Pediatrics, University Hospital RWTH Aachen, Aachen, Germany
| | | | - Christian Trautwein
- Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany
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Ferjani Z, Bouzid D, Fourati H, Fakhfakh R, Kammoun T, Hachicha M, Penha-Gonçalves C, Masmoudi H. WITHDRAWN: CREM variant rs17583959 conferred susceptibility to T1D risk in the Tunisian families. GENE REPORTS 2017; 6:116-120. [DOI: 10.1016/j.genrep.2016.11.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/07/2022]
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Zouidi F, Bouzid D, Fourati H, Fakhfakh R, Kammoun T, Hachicha M, Penha-Gonçalves C, Masmoudi H. CREM variant rs17583959 conferred susceptibility to T1D risk in the Tunisian families. Immunol Lett 2017; 181:1-5. [PMID: 27840176 DOI: 10.1016/j.imlet.2016.11.007] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2015] [Revised: 11/09/2016] [Accepted: 11/09/2016] [Indexed: 12/17/2022]
Abstract
Type 1 diabetes mellitus (T1D) is a chronic autoimmune disease caused by the destruction of insulin-producing pancreatic β-cells by autoreactive T cells. Studies in animal models, such as the non-obese diabetic (NOD) mouse reveal that this disease is under the control of several genes that encode molecules implicated in regulation of transcription factors and in T cell activation. In order to underline the role of the genes involved in this regulation pathways, we investigated, using the Sequenom MassARRAY platform, 13 single-nucleotide polymorphisms (SNPs) belonging to CREM, IRF5, STAT4, and STAT5a/b genes in 59 T1D Tunisian families. In the current study, we identified an association with rs17583959 (allele G; Z score=2.27; p=0.02; Genotype GG: score=1.96; p=0.04) of CREM gene. In LD analysis a strong LD between the 3 CREM variants (Block 1) was detected; rs2384352 was in complete LD with rs1148247. When haplotypes were constructed between CREM polymorphisms (rs1148247, rs17583959, rs2384352), AGA haplotype (H2) was significantly over-transmitted from parents to affected offspring (Z score=2.988; P=0.002) and may confer a risk for T1D disease. Whereas, AAG haplotype (H5) (Z score=-2.000; p=0.045) was less transmitted than expected to affected children suggesting its protective effect against T1D pathology. No significant association in IRF5, STAT4, and STAT5a/b genes were observed. In conclusion, this study shows an eventually involvement of CREM gene in the development of T1D pathology in Tunisian families. These facts are consistent with a major role for transcription factor genes involved in the immune pathways in the control of autoimmunity. Further researches of association and functional analysis across populations are needed to confirm these findings.
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Affiliation(s)
- Ferjani Zouidi
- Immunology Department, Habib Bourguiba Hospital, University of Sfax, Tunisie.
| | - D Bouzid
- Immunology Department, Habib Bourguiba Hospital, University of Sfax, Tunisie
| | - H Fourati
- Immunology Department, Habib Bourguiba Hospital, University of Sfax, Tunisie
| | - R Fakhfakh
- Immunology Department, Habib Bourguiba Hospital, University of Sfax, Tunisie
| | - T Kammoun
- Pediatric Department, Hedi Chaker Hospital, Sfax, Tunisie
| | - M Hachicha
- Pediatric Department, Hedi Chaker Hospital, Sfax, Tunisie
| | | | - H Masmoudi
- Immunology Department, Habib Bourguiba Hospital, University of Sfax, Tunisie
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26
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Boros P, Ochando J, Zeher M. Myeloid derived suppressor cells and autoimmunity. Hum Immunol 2016; 77:631-636. [DOI: 10.1016/j.humimm.2016.05.024] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2016] [Revised: 05/26/2016] [Accepted: 05/26/2016] [Indexed: 12/13/2022]
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Abstract
The liver is a central immunological organ with a high exposure to circulating antigens and endotoxins from the gut microbiota, particularly enriched for innate immune cells (macrophages, innate lymphoid cells, mucosal-associated invariant T (MAIT) cells). In homeostasis, many mechanisms ensure suppression of immune responses, resulting in tolerance. Tolerance is also relevant for chronic persistence of hepatotropic viruses or allograft acceptance after liver transplantation. The liver can rapidly activate immunity in response to infections or tissue damage. Depending on the underlying liver disease, such as viral hepatitis, cholestasis or NASH, different triggers mediate immune-cell activation. Conserved mechanisms such as molecular danger patterns (alarmins), Toll-like receptor signalling or inflammasome activation initiate inflammatory responses in the liver. The inflammatory activation of hepatic stellate and Kupffer cells results in the chemokine-mediated infiltration of neutrophils, monocytes, natural killer (NK) and natural killer T (NKT) cells. The ultimate outcome of the intrahepatic immune response (for example, fibrosis or resolution) depends on the functional diversity of macrophages and dendritic cells, but also on the balance between pro-inflammatory and anti-inflammatory T-cell populations. As reviewed here, tremendous progress has helped to understand the fine-tuning of immune responses in the liver from homeostasis to disease, indicating promising targets for future therapies in acute and chronic liver diseases.
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Affiliation(s)
- Felix Heymann
- Department of Medicine III, RWTH University-Hospital Aachen, Pauwelsstrasse 30, Aachen 52074, Germany
| | - Frank Tacke
- Department of Medicine III, RWTH University-Hospital Aachen, Pauwelsstrasse 30, Aachen 52074, Germany
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Hammerich L, Tacke F. Emerging roles of myeloid derived suppressor cells in hepatic inflammation and fibrosis. World J Gastrointest Pathophysiol 2015; 6:43-50. [PMID: 26301117 PMCID: PMC4540705 DOI: 10.4291/wjgp.v6.i3.43] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2015] [Revised: 03/16/2015] [Accepted: 06/02/2015] [Indexed: 02/06/2023] Open
Abstract
Myeloid derived suppressor cells (MDSC) are a heterogeneous population of immune cells that are potent suppressors of immune responses. MDSC emerge in various compartments in the body, such as blood, bone marrow or spleen, especially in conditions of cancer, infections or inflammation. MDSC usually express CD11b, CD33, and low levels of human leukocyte antigen-DR in humans or CD11b and Gr1 (Ly6C/G) in mice, and they can be further divided into granulocytic or monocytic MDSC. The liver is an important organ for MDSC induction and accumulation in hepatic as well as extrahepatic diseases. Different hepatic cells, especially hepatic stellate cells, as well as liver-derived soluble factors, including hepatocyte growth factor and acute phase proteins (SAA, KC), can promote the differentiation of MDSC from myeloid cells. Importantly, hepatic myeloid cells like neutrophils, monocytes and macrophages fulfill essential roles in acute and chronic liver diseases. Recent data from patients with liver diseases and animal models linked MDSC to the pathogenesis of hepatic inflammation, fibrosis and hepatocellular carcinoma (HCC). In settings of acute hepatitis, MDSC can limit immunogenic T cell responses and subsequent tissue injury. In patients with chronic hepatitis C, MDSC increase and may favor viral persistence. Animal models of chronic liver injury, however, have not yet conclusively clarified the involvement of MDSC for hepatic fibrosis. In human HCC and mouse models of liver cancer, MDSC are induced in the tumor environment and suppress anti-tumoral immune responses. Thus, the liver is a primary site of MDSC in vivo, and modulating MDSC functionality might represent a promising novel therapeutic target for liver diseases.
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The Role and Potential Therapeutic Application of Myeloid-Derived Suppressor Cells in Allo- and Autoimmunity. Mediators Inflamm 2015; 2015:421927. [PMID: 26078493 PMCID: PMC4452474 DOI: 10.1155/2015/421927] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2015] [Revised: 04/21/2015] [Accepted: 04/28/2015] [Indexed: 12/16/2022] Open
Abstract
Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of cells that consists of myeloid progenitor cells and immature myeloid cells. They have been identified as a cell population that may affect the activation of CD4(+) and CD8(+) T-cells to regulate the immune response negatively, which makes them attractive targets for the treatment of transplantation and autoimmune diseases. Several studies have suggested the potential suppressive effect of MDSCs on allo- and autoimmune responses. Conversely, MDSCs have also been found at various stages of differentiation, accumulating during pathological situations, not only during tumor development but also in a variety of inflammatory immune responses, bone marrow transplantation, and some autoimmune diseases. These findings appear to be contradictory. In this review, we summarize the roles of MDSCs in different transplantation and autoimmune diseases models as well as the potential to target these cells for therapeutic benefit.
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