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1
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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] [MESH Headings] [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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Yang A, Zhou M, Gao Y, Zhang Y. Mechanisms of CD8 + T cell exhaustion and its clinical significance in prognosis of anti-tumor therapies: A review. Int Immunopharmacol 2025; 159:114843. [PMID: 40394796 DOI: 10.1016/j.intimp.2025.114843] [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: 12/09/2024] [Revised: 05/05/2025] [Accepted: 05/08/2025] [Indexed: 05/22/2025]
Abstract
In recent years, immunotherapy has gradually become one of the main strategies for cancer treatment, with immune checkpoint inhibitors (ICIs) offering new possibilities for tumor therapy. However, some cancer patients exhibit low responses and resistance to ICIs treatment. T cell exhaustion, a process associated with tumor progression, refers to a subset of T cells that progressively lose effector functions and exhibit increased expression of inhibitory receptors. These exhausted T cells are considered key players in the therapeutic efficacy of immune checkpoint inhibitors. Therefore, understanding the impact of T cell exhaustion on tumor immunotherapy and the underlying mechanisms is critical for improving clinical treatment outcomes. Several elegant studies have provided insights into the prognostic value of exhausted T cells in cancers. In this review, we highlight the process of exhausted T cells and its predictive value in various cancers, as well as the relevant mechanisms behind it, providing new insights into the immunotherapy of cancer.
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Affiliation(s)
- Anrui Yang
- Department of Gynecological Minimal Invasive Center, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China
| | - Meng Zhou
- Department of Gynecological Minimal Invasive Center, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China
| | - Yixuan Gao
- Department of Gynecological Minimal Invasive Center, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China
| | - Ying Zhang
- Department of Gynecological Minimal Invasive Center, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China.
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3
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Sererols-Viñas L, Garcia-Vicién G, Ruiz-Blázquez P, Lee TF, Lee YA, Gonzalez-Sanchez E, Vaquero J, Moles A, Filliol A, Affò S. Hepatic Stellate Cells Functional Heterogeneity in Liver Cancer. Semin Liver Dis 2025; 45:33-51. [PMID: 40043738 DOI: 10.1055/a-2551-0724] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/01/2025]
Abstract
Hepatic stellate cells (HSCs) are the liver's pericytes, and play key roles in liver homeostasis, regeneration, fibrosis, and cancer. Upon injury, HSCs activate and are the main origin of myofibroblasts and cancer-associated fibroblasts (CAFs) in liver fibrosis and cancer. Primary liver cancer has a grim prognosis, ranking as the third leading cause of cancer-related deaths worldwide, with hepatocellular carcinoma (HCC) being the predominant type, followed by intrahepatic cholangiocarcinoma (iCCA). Moreover, the liver hosts 35% of all metastatic lesions. The distinct spatial distribution and functional roles of HSCs across these malignancies represent a significant challenge for universal therapeutic strategies, requiring a nuanced and tailored understanding of their contributions. This review examines the heterogeneous roles of HSCs in liver cancer, focusing on their spatial localization, dynamic interactions within the tumor microenvironment (TME), and emerging therapeutic opportunities, including strategies to modulate their activity, and harness their potential as targets for antifibrotic and antitumor interventions.
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Affiliation(s)
- Laura Sererols-Viñas
- Tumor Microenvironment Plasticity and Heterogeneity Research Group, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- University of Barcelona, Barcelona, Spain
| | - Gemma Garcia-Vicién
- Tumor Microenvironment Plasticity and Heterogeneity Research Group, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Paloma Ruiz-Blázquez
- University of Barcelona, Barcelona, Spain
- Tissue Remodeling Fibrosis and Cancer Group, Institute of Biomedical Research of Barcelona, Spanish National Research Council, Barcelona, Spain
- Institute of Biomedical Research of Barcelona (IDIBAPS), Barcelona, Spain
- CIBEREHD, National Biomedical Research Institute on Liver and Gastrointestinal Diseases, Instituto de Salud Carlos III, Madrid, Spain
| | - Ting-Fang Lee
- Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Youngmin A Lee
- Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Ester Gonzalez-Sanchez
- HepatoBiliary Tumours Lab, Centro de Investigación del Cáncer and Instituto de Biología Molecular y Celular del Cáncer, CSIC-Universidad de Salamanca, Salamanca, Spain
- Department of Physiology and Pharmacology, University of Salamanca, Salamanca, Spain
| | - Javier Vaquero
- CIBEREHD, National Biomedical Research Institute on Liver and Gastrointestinal Diseases, Instituto de Salud Carlos III, Madrid, Spain
- HepatoBiliary Tumours Lab, Centro de Investigación del Cáncer and Instituto de Biología Molecular y Celular del Cáncer, CSIC-Universidad de Salamanca, Salamanca, Spain
- TGF-β and Cancer Group, Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain
| | - Anna Moles
- Tissue Remodeling Fibrosis and Cancer Group, Institute of Biomedical Research of Barcelona, Spanish National Research Council, Barcelona, Spain
- Institute of Biomedical Research of Barcelona (IDIBAPS), Barcelona, Spain
- CIBEREHD, National Biomedical Research Institute on Liver and Gastrointestinal Diseases, Instituto de Salud Carlos III, Madrid, Spain
| | - Aveline Filliol
- Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Silvia Affò
- Tumor Microenvironment Plasticity and Heterogeneity Research Group, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
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4
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Hagenstein J, Burkhardt S, Sprezyna P, Tasika E, Tiegs G, Diehl L. CD44 expression on murine hepatic stellate cells promotes the induction of monocytic and polymorphonuclear myeloid-derived suppressor cells. J Leukoc Biol 2024; 116:177-185. [PMID: 38484149 DOI: 10.1093/jleuko/qiae053] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Revised: 01/31/2024] [Accepted: 02/22/2024] [Indexed: 06/30/2024] Open
Abstract
In chronic inflammation, regulatory immune cells, such as regulatory T cells and myeloid-derived suppressor cells, can develop. Local signals in the inflamed tissue, such as cytokines and eicosanoids, but also contact-dependent signals, can promote myeloid-derived suppressor cell development. In the liver, hepatic stellate cells may provide such signals via the expression of CD44. Myeloid-derived suppressor cells generated in the presence of hepatic stellate cells and anti-CD44 antibodies were functionally and phenotypically analyzed. We found that both monocytic and polymorphonuclear myeloid-derived suppressor cells generated in the presence of αCD44 antibodies were less suppressive toward T cells as measured by T-cell proliferation and cytokine production. Moreover, both monocytic and polymorphonuclear myeloid-derived suppressor cells were phenotypically altered. Monocytic myeloid-derived suppressor cells mainly changed their expression of CD80 and CD39, and polymorphonuclear myeloid-derived suppressor cells showed altered expression of CD80/86, PD-L1, and CCR2. Moreover, both polymorphonuclear and monocytic myeloid-derived suppressor cells lost expression of Nos2 messenger RNA, whereas monocytic myeloid-derived suppressor cells showed reduced expression of TGFb messenger RNA and polymorphonuclear myeloid-derived suppressor cells reduced expression of Il10 messenger RNA. In summary, the presence of CD44 in hepatic stellate cells promotes the induction of both monocytic and polymorphonuclear myeloid-derived suppressor cells, although the mechanisms by which these myeloid-derived suppressor cells may increase suppressive function due to interaction with CD44 are only partially overlapping.
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Affiliation(s)
- Julia Hagenstein
- Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany
- Hamburg Center of Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany
| | - Simon Burkhardt
- Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany
- Hamburg Center of Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany
| | - Paulina Sprezyna
- Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany
- Hamburg Center of Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany
| | - Elena Tasika
- Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany
- Hamburg Center of Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany
| | - Gisa Tiegs
- Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany
- Hamburg Center of Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany
| | - Linda Diehl
- Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany
- Hamburg Center of Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany
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Salminen A, Kaarniranta K, Kauppinen A. Tissue fibroblasts are versatile immune regulators: An evaluation of their impact on the aging process. Ageing Res Rev 2024; 97:102296. [PMID: 38588867 DOI: 10.1016/j.arr.2024.102296] [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: 12/18/2023] [Revised: 03/26/2024] [Accepted: 04/03/2024] [Indexed: 04/10/2024]
Abstract
Fibroblasts are abundant stromal cells which not only control the integrity of extracellular matrix (ECM) but also act as immune regulators. It is known that the structural cells within tissues can establish an organ-specific immunity expressing many immune-related genes and closely interact with immune cells. In fact, fibroblasts can modify their immune properties to display both pro-inflammatory and immunosuppressive activities in a context-dependent manner. After acute insults, fibroblasts promote tissue inflammation although they concurrently recruit immunosuppressive cells to enhance the resolution of inflammation. In chronic pathological states, tissue fibroblasts, especially senescent fibroblasts, can display many pro-inflammatory and immunosuppressive properties and stimulate the activities of different immunosuppressive cells. In return, immunosuppressive cells, such as M2 macrophages and myeloid-derived suppressor cells (MDSC), evoke an excessive conversion of fibroblasts into myofibroblasts, thus aggravating the severity of tissue fibrosis. Single-cell transcriptome studies on fibroblasts isolated from aged tissues have confirmed that tissue fibroblasts express many genes coding for cytokines, chemokines, and complement factors, whereas they lose some fibrogenic properties. The versatile immune properties of fibroblasts and their close cooperation with immune cells indicate that tissue fibroblasts have a crucial role in the aging process and age-related diseases.
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Affiliation(s)
- Antero Salminen
- Department of Neurology, Institute of Clinical Medicine, University of Eastern Finland, P.O. Box 1627, Kuopio FI-70211, Finland.
| | - Kai Kaarniranta
- Department of Ophthalmology, Institute of Clinical Medicine, University of Eastern Finland, P.O. Box 1627, Kuopio FI-70211, Finland; Department of Ophthalmology, Kuopio University Hospital, P.O. Box 100, KYS FI-70029, Finland
| | - Anu Kauppinen
- School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, Kuopio FI-70211, Finland
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Zhang Q, Yu T, Tan H, Shi H. Hepatic recruitment of myeloid-derived suppressor cells upon liver injury promotes both liver regeneration and fibrosis. BMC Gastroenterol 2024; 24:163. [PMID: 38745150 PMCID: PMC11092103 DOI: 10.1186/s12876-024-03245-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Accepted: 04/29/2024] [Indexed: 05/16/2024] Open
Abstract
BACKGROUND The liver regeneration is a highly complicated process depending on the close cooperations between the hepatocytes and non-parenchymal cells involving various inflammatory cells. Here, we explored the role of myeloid-derived suppressor cells (MDSCs) in the processes of liver regeneration and liver fibrosis after liver injury. METHODS We established four liver injury models of mice including CCl4-induced liver injury model, bile duct ligation (BDL) model, concanavalin A (Con A)-induced hepatitis model, and lipopolysaccharide (LPS)-induced hepatitis model. The intrahepatic levels of MDSCs (CD11b+Gr-1+) after the liver injury were detected by flow cytometry. The effects of MDSCs on liver tissues were analyzed in the transwell co-culture system, in which the MDSCs cytokines including IL-10, VEGF, and TGF-β were measured by ELISA assay and followed by being blocked with specific antibodies. RESULTS The intrahepatic infiltrations of MDSCs with surface marker of CD11b+Gr-1+ remarkably increased after the establishment of four liver injury models. The blood served as the primary reservoir for hepatic recruitment of MDSCs during the liver injury, while the bone marrow appeared play a compensated role in increasing the number of MDSCs at the late stage of the inflammation. The recruited MDSCs in injured liver were mainly the M-MDSCs (CD11b+Ly6G-Ly6Chigh) featured by high expression levels of cytokines including IL-10, VEGF, and TGF-β. Co-culture of the liver tissues with MDSCs significantly promoted the proliferation of both hepatocytes and hepatic stellate cells (HSCs). CONCLUSIONS The dramatically and quickly infiltrated CD11b+Gr-1+ MDSCs in injured liver not only exerted pro-proliferative effects on hepatocytes, but also accounted for the activation of profibrotic HSCs.
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Affiliation(s)
- Qiongwen Zhang
- Department of Head and Neck Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, P.R. China
| | - Ting Yu
- Department of Pathology, West China Hospital, Sichuan University, Chengdu, Sichuan, P.R. China
| | - Huaicheng Tan
- Department of Head and Neck Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, P.R. China
| | - Huashan Shi
- Department of Head and Neck Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, P.R. China.
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7
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Chen J, Chan TTH, Zhou J. Lipid metabolism in the immune niche of tumor-prone liver microenvironment. J Leukoc Biol 2024; 115:68-84. [PMID: 37474318 DOI: 10.1093/jleuko/qiad081] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2023] [Revised: 06/23/2023] [Accepted: 07/06/2023] [Indexed: 07/22/2023] Open
Abstract
The liver is a common primary site not only for tumorigenesis, but also for cancer metastasis. Advanced cancer patients with liver metastases also show reduced response rates and survival benefits when treated with immune checkpoint inhibitors. Accumulating evidence has highlighted the importance of the liver immune microenvironment in determining tumorigenesis, metastasis-organotropism, and immunotherapy resistance. Various immune cells such as T cells, natural killer and natural killer T cells, macrophages and dendritic cells, and stromal cells including liver sinusoidal endothelial cells, Kupffer cells, hepatic stellate cells, and hepatocytes are implicated in contributing to the immune niche of tumor-prone liver microenvironment. In parallel, as the major organ for lipid metabolism, the increased abundance of lipids and their metabolites is linked to processes crucial for nonalcoholic fatty liver disease and related liver cancer development. Furthermore, the proliferation, differentiation, and functions of hepatic immune and stromal cells are also reported to be regulated by lipid metabolism. Therefore, targeting lipid metabolism may hold great potential to reprogram the immunosuppressive liver microenvironment and synergistically enhance the immunotherapy efficacy in the circumstance of liver metastasis. In this review, we describe how the hepatic microenvironment adapts to the lipid metabolic alterations in pathologic conditions like nonalcoholic fatty liver disease. We also illustrate how these immunometabolic alterations promote the development of liver cancers and immunotherapy resistance. Finally, we discuss the current therapeutic options and hypothetic combination immunotherapies for the treatment of advanced liver cancers.
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Affiliation(s)
- Jintian Chen
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong 999077, SAR, P.R. China
| | - Thomas T H Chan
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong 999077, SAR, P.R. China
| | - Jingying Zhou
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong 999077, SAR, P.R. China
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8
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Porto E, De Backer J, Thuy LTT, Kawada N, Hankeln T. Transcriptomics of a cytoglobin knockout mouse: Insights from hepatic stellate cells and brain. J Inorg Biochem 2024; 250:112405. [PMID: 37977965 DOI: 10.1016/j.jinorgbio.2023.112405] [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: 06/12/2023] [Revised: 10/10/2023] [Accepted: 10/16/2023] [Indexed: 11/19/2023]
Abstract
The vertebrate respiratory protein cytoglobin (Cygb) is thought to exert multiple cellular functions. Here we studied the phenotypic effects of a Cygb knockout (KO) in mouse on the transcriptome level. RNA sequencing (RNA-Seq) was performed for the first time on sites of major endogenous Cygb expression, i.e. quiescent and activated hepatic stellate cells (HSCs) and two brain regions, hippocampus and hypothalamus. The data recapitulated the up-regulation of Cygb during HSC activation and its expression in the brain. Differential gene expression analyses suggested a role of Cygb in the response to inflammation in HSCs and its involvement in retinoid metabolism, retinoid X receptor (RXR) activation-induced xenobiotics metabolism, and RXR activation-induced lipid metabolism and signaling in activated cells. Unexpectedly, only minor effects of the Cygb KO were detected in the transcriptional profiles in hippocampus and hypothalamus, precluding any enrichment analyses. Furthermore, the transcriptome data pointed at a previously undescribed potential of the Cygb- knockout allele to produce cis-acting effects, necessitating future verification studies.
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Affiliation(s)
- Elena Porto
- Institute of Organismic and Molecular Evolution, Molecular Genetics & Genome Analysis Group, Johannes Gutenberg University Mainz, J. J. Becher-Weg 30A, Mainz D-55128, Germany
| | - Joey De Backer
- Research Group PPES, Department of Biomedical Sciences, University of Antwerp, Universiteitsplein 1, Wilrijk, Antwerp 1610, Belgium
| | - Le Thi Thanh Thuy
- Department of Hepatology, Graduate School of Medicine, Osaka Metropolitan University, Osaka 545-8585, Japan
| | - Norifumi Kawada
- Department of Hepatology, Graduate School of Medicine, Osaka Metropolitan University, Osaka 545-8585, Japan
| | - Thomas Hankeln
- Institute of Organismic and Molecular Evolution, Molecular Genetics & Genome Analysis Group, Johannes Gutenberg University Mainz, J. J. Becher-Weg 30A, Mainz D-55128, Germany.
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9
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Li TT, Lin CL, Chiang M, He JT, Hung CH, Hsieh CC. Cytokine-Induced Myeloid-Derived Suppressor Cells Demonstrate Their Immunoregulatory Functions to Prolong the Survival of Diabetic Mice. Cells 2023; 12:1507. [PMID: 37296628 PMCID: PMC10253032 DOI: 10.3390/cells12111507] [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: 04/04/2023] [Revised: 05/21/2023] [Accepted: 05/26/2023] [Indexed: 06/12/2023] Open
Abstract
Type 1 diabetes is an inflammatory state. Myeloid-derived suppressive cells (MDSCs) originate from immature myeloid cells and quickly expand to control host immunity during infection, inflammation, trauma, and cancer. This study presents an ex vivo procedure to develop MDSCs from bone marrow cells propagated from granulocyte-macrophage-colony-stimulating factor (GM-CSF), interleukin (IL)-6, and IL-1β cytokines expressing immature morphology and high immunosuppression of T-cell proliferation. The adoptive transfer of cytokine-induced MDSCs (cMDSCs) improved the hyperglycemic state and prolonged the diabetes-free survival of nonobese diabetic (NOD) mice with severe combined immune deficiency (SCID) induced by reactive splenic T cells harvested from NOD mice. In addition, the application of cMDSCs reduced fibronectin production in the renal glomeruli and improved renal function and proteinuria in diabetic mice. Moreover, cMDSCs use mitigated pancreatic insulitis to restore insulin production and reduce the levels of HbA1c. In conclusion, administering cMDSCs propagated from GM-CSF, IL-6, and IL-1β cytokines provides an alternative immunotherapy protocol for treating diabetic pancreatic insulitis and renal nephropathy.
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Affiliation(s)
- Tung-Teng Li
- Division of General Surgery, Chang-Gung Memorial Hospital, Chiayi 61302, Taiwan; (T.-T.L.)
| | - Chun-Liang Lin
- Department of Nephrology, Chang-Gung Memorial Hospital, Chiayi 61302, Taiwan;
- Kidney and Diabetic Complications Research Team (KDCRT), Chang-Gung Memorial Hospital, Chiayi 61302, Taiwan
- College of Medicine, Chang-Gung University, Taoyuan 33302, Taiwan
| | - Meihua Chiang
- Division of General Surgery, Chang-Gung Memorial Hospital, Chiayi 61302, Taiwan; (T.-T.L.)
| | - Jie-Teng He
- Division of General Surgery, Chang-Gung Memorial Hospital, Chiayi 61302, Taiwan; (T.-T.L.)
| | - Chien-Hui Hung
- College of Medicine, Chang-Gung University, Taoyuan 33302, Taiwan
- Division of Infectious Diseases, Chang-Gung Memorial Hospital, Chiayi 61302, Taiwan
| | - Ching-Chuan Hsieh
- Division of General Surgery, Chang-Gung Memorial Hospital, Chiayi 61302, Taiwan; (T.-T.L.)
- Kidney and Diabetic Complications Research Team (KDCRT), Chang-Gung Memorial Hospital, Chiayi 61302, Taiwan
- College of Medicine, Chang-Gung University, Taoyuan 33302, Taiwan
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10
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Wiering L, Subramanian P, Hammerich L. Hepatic Stellate Cells: Dictating Outcome in Nonalcoholic Fatty Liver Disease. Cell Mol Gastroenterol Hepatol 2023; 15:1277-1292. [PMID: 36828280 PMCID: PMC10148161 DOI: 10.1016/j.jcmgh.2023.02.010] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 02/15/2023] [Accepted: 02/15/2023] [Indexed: 02/26/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a fast growing, chronic liver disease affecting ∼25% of the global population. Nonalcoholic fatty liver disease severity ranges from the less severe simple hepatic steatosis to the more advanced nonalcoholic steatohepatitis (NASH). The presence of NASH predisposes individuals to liver fibrosis, which can further progress to cirrhosis and hepatocellular carcinoma. This makes hepatic fibrosis an important indicator of clinical outcomes in patients with NASH. Hepatic stellate cell activation dictates fibrosis development during NASH. Here, we discuss recent advances in the analysis of the profibrogenic pathways and mediators of hepatic stellate cell activation and inactivation, which ultimately determine the course of disease in nonalcoholic fatty liver disease/NASH.
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Affiliation(s)
- Leke Wiering
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum and Campus Charité Mitte, Berlin, Germany; Berlin Institute of Health at Charité - Universitätsmedizin Berlin, BIH Biomedical Innovation Academy, BIH Charité Junior Clinician Scientist Program, Berlin, Germany
| | - Pallavi Subramanian
- Institute for Clinical Chemistry and Laboratory Medicine, University Hospital and Faculty of Medicine, Technische Universität Dresden, Dresden, Germany
| | - Linda Hammerich
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum and Campus Charité Mitte, Berlin, Germany.
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11
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Ezhilarasan D, Najimi M. Deciphering the possible reciprocal loop between hepatic stellate cells and cancer cells in the tumor microenvironment of the liver. Crit Rev Oncol Hematol 2023; 182:103902. [PMID: 36621514 DOI: 10.1016/j.critrevonc.2022.103902] [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: 10/07/2022] [Revised: 12/22/2022] [Accepted: 12/23/2022] [Indexed: 01/07/2023] Open
Abstract
Activated hepatic stellate cells (HSCs)/myofibroblasts are the important sources of cancer-associated fibroblasts in the liver tumor microenvironment (TME). The crosstalk between activated HSCs and tumor cells mediates HCC progression, metastasis, tumor cell survival, angiogenesis and chemoresistance. In TME, HCC cells secrete various soluble factors responsible for the phenotypic activation of quiescent HSCs. Tumor cells use activated HSC-derived extracellular matrix (ECM) for migration and invasion. Further, in liver TME, activated HSCs and sinusoidal endothelial cells engage in a crosstalk that causes the secretion of angiogenesis and metastasis-related growth factors and cytokines. Activated HSCs and immune cells crosstalk to decrease immune surveillance in the liver TME by increasing the population of T regulatory cells and M2 macrophages or myeloid-derived suppressor cells. Thus, HSCs play a vital role in liver TME cell interactions. Therefore, a deep understanding of HSCs activation and their crosstalk with cancer and immune cells in TME may lead to the development of novel therapeutic strategies to target HCC.
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Affiliation(s)
- Devaraj Ezhilarasan
- Department of Pharmacology, Saveetha Dental College, Saveetha Institute of Medical and Technical Sciences, Chennai, Tamil Nadu 600077, India.
| | - Mustapha Najimi
- Laboratory of Pediatric Hepatology and Cell Therapy, Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain, Brussels 1200, Belgium
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12
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Xu D, Li C, Xu Y, Huang M, Cui D, Xie J. Myeloid-derived suppressor cell: A crucial player in autoimmune diseases. Front Immunol 2022; 13:1021612. [PMID: 36569895 PMCID: PMC9780445 DOI: 10.3389/fimmu.2022.1021612] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Accepted: 11/24/2022] [Indexed: 12/13/2022] Open
Abstract
Myeloid-derived suppressor cells (MDSCs) are identified as a highly heterogeneous group of immature cells derived from bone marrow and play critical immunosuppressive functions in autoimmune diseases. Accumulating evidence indicates that the pathophysiology of autoimmune diseases was closely related to genetic mutations and epigenetic modifications, with the latter more common. Epigenetic modifications, which involve DNA methylation, covalent histone modification, and non-coding RNA-mediated regulation, refer to inheritable and potentially reversible changes in DNA and chromatin that regulate gene expression without altering the DNA sequence. Recently, numerous reports have shown that epigenetic modifications in MDSCs play important roles in the differentiation and development of MDSCs and their suppressive functions. The molecular mechanisms of differentiation and development of MDSCs and their regulatory roles in the initiation and progression of autoimmune diseases have been extensively studied, but the exact function of MDSCs remains controversial. Therefore, the biological and epigenetic regulation of MDSCs in autoimmune diseases still needs to be further characterized. This review provides a detailed summary of the current research on the regulatory roles of DNA methylation, histone modifications, and non-coding RNAs in the development and immunosuppressive activity of MDSCs, and further summarizes the distinct role of MDSCs in the pathogenesis of autoimmune diseases, in order to provide help for the diagnosis and treatment of diseases from the perspective of epigenetic regulation of MDSCs.
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Affiliation(s)
- Dandan Xu
- Department of Blood Transfusion, The First Affiliated Hospital, School of Medicine, Hangzhou, Zhejiang University, China
| | - Cheng Li
- School of Medicine, Southern University of Science and Technology, Shenzhen, China
| | - Yushan Xu
- Department of Blood Transfusion, The First Affiliated Hospital, School of Medicine, Hangzhou, Zhejiang University, China
| | - Mingyue Huang
- School of Medicine, Southern University of Science and Technology, Shenzhen, China
| | - Dawei Cui
- Department of Blood Transfusion, The First Affiliated Hospital, School of Medicine, Hangzhou, Zhejiang University, China,*Correspondence: Dawei Cui, ; Jue Xie,
| | - Jue Xie
- Department of Blood Transfusion, The First Affiliated Hospital, School of Medicine, Hangzhou, Zhejiang University, China,*Correspondence: Dawei Cui, ; Jue Xie,
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13
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Schroeter A, Roesel MJ, Matsunaga T, Xiao Y, Zhou H, Tullius SG. Aging Affects the Role of Myeloid-Derived Suppressor Cells in Alloimmunity. Front Immunol 2022; 13:917972. [PMID: 35874716 PMCID: PMC9296838 DOI: 10.3389/fimmu.2022.917972] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Accepted: 06/07/2022] [Indexed: 11/16/2022] Open
Abstract
Myeloid-derived suppressor cells (MDSC) are defined as a group of myeloid cells with potent immunoregulatory functions that have been shown to be involved in a variety of immune-related diseases including infections, autoimmune disorders, and cancer. In organ transplantation, MDSC promote tolerance by modifying adaptive immune responses. With aging, however, substantial changes occur that affect immune functions and impact alloimmunity. Since the vast majority of transplant patients are elderly, age-specific modifications of MDSC are of relevance. Furthermore, understanding age-associated changes in MDSC may lead to improved therapeutic strategies. Here, we provide a comprehensive update on the effects of aging on MDSC and discuss potential consequences on alloimmunity.
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Affiliation(s)
- Andreas Schroeter
- Transplant Surgery Research Laboratory and Division of Transplant Surgery, Department of Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
- Regenerative Medicine and Experimental Surgery, Department of General, Visceral and Transplant Surgery, Hannover Medical School, Hannover, Germany
| | - Maximilian J. Roesel
- Transplant Surgery Research Laboratory and Division of Transplant Surgery, Department of Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
- Institute of Medical Immunology, Charite Universitaetsmedizin Berlin, Berlin, Germany
| | - Tomohisa Matsunaga
- Transplant Surgery Research Laboratory and Division of Transplant Surgery, Department of Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
- Department of Urology, Osaka Medical and Pharmaceutical University, Takatsuki City, Japan
| | - Yao Xiao
- Transplant Surgery Research Laboratory and Division of Transplant Surgery, Department of Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
| | - Hao Zhou
- Transplant Surgery Research Laboratory and Division of Transplant Surgery, Department of Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
| | - Stefan G. Tullius
- Transplant Surgery Research Laboratory and Division of Transplant Surgery, Department of Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
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14
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Abstract
Patients with chronic hepatitis B (CHB) represent a living and permanent reservoir of hepatitis B virus (HBV). Millions of these CHB patients will eventually develop complications such as liver cirrhosis, hepatic failure, and hepatocellular carcinoma if they are not treated properly. Accordingly, several antiviral drugs have been developed for the treatment of CHB, but these drugs can neither eradicate all forms of HBV nor contain the progression of complications in most patients with CHB. Thus, the development of new and novel therapeutics for CHB remains a pressing need. The molecular and cellular mechanisms underlying the pathogenesis of CHB indicate that immune dysregulations may be responsible for HBV persistence and progressive liver damage in CHB. This provided the scientific and ethical basis for the immune therapy of CHB patients. Around 30 years have passed since the initiation of immune therapies for CHB in the early 1990s, and hundreds of clinical trials have been accomplished to substantiate this immune treatment. Despite these approaches, an acceptable regimen of immune therapy is yet to be realized. However, most immune therapeutic agents are safe for human usage, and many of these protocols have inspired considerable optimism. In this review, the pros and cons of different immune therapies, observed in patients with CHB during the last 30 years, will be discussed to derive insights into the development of an evidence-based, effective, and patient-friendly regimen of immune therapy for the treatment of CHB.
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Affiliation(s)
- Sheikh Mohammad Fazle Akbar
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Shitsukawa 454, Toon City, Ehime, 791-0295, Japan.
| | - Osamu Yoshida
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Shitsukawa 454, Toon City, Ehime, 791-0295, Japan
| | - Yoichi Hiasa
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Shitsukawa 454, Toon City, Ehime, 791-0295, Japan
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15
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Carter JK, Friedman SL. Hepatic Stellate Cell-Immune Interactions in NASH. Front Endocrinol (Lausanne) 2022; 13:867940. [PMID: 35757404 PMCID: PMC9218059 DOI: 10.3389/fendo.2022.867940] [Citation(s) in RCA: 50] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Accepted: 04/29/2022] [Indexed: 02/06/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the dominant cause of liver disease worldwide. Nonalcoholic steatohepatitis (NASH), a more aggressive presentation of NAFLD, is characterized by severe hepatocellular injury, inflammation, and fibrosis. Chronic inflammation and heightened immune cell activity have emerged as hallmark features of NASH and key drivers of fibrosis through the activation of hepatic stellate cells (HSCs). Recent advances in our understanding of the molecular and cellular pathways in NASH have highlighted extensive crosstalk between HSCs and hepatic immune populations that strongly influences disease activity. Here, we review these findings, emphasizing the roles of HSCs in liver immunity and inflammation, key cell-cell interactions, and exciting areas for future investigation.
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Affiliation(s)
- James K Carter
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, United States
- Medical Scientist Training Program, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Scott L Friedman
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, United States
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16
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Role of Myeloid-derived suppressor cell (MDSC) in autoimmunity and its potential as a therapeutic target. Inflammopharmacology 2021; 29:1307-1315. [PMID: 34283371 DOI: 10.1007/s10787-021-00846-3] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Accepted: 07/04/2021] [Indexed: 02/07/2023]
Abstract
Myeloid suppressor cells (MDSCs) are an important class of immune-regulating cells that can suppress T cell function. Most of our knowledge about the function of MDSC comes from studies of cancer models. Recent studies, however, have greatly contributed to the description of MDSC involvement in autoimmune diseases. They are known as a cell population that may negatively affect immune responses by regulating the function of CD4+ and CD8+ cells, which makes them an attractive target for autoimmune diseases therapy. However, many questions about MDSC activation, differentiation, and inhibitory functions remain unanswered. In this study, we have summarized the role of MDSCs in various autoimmune diseases, and the potential of targeting them for therapeutic benefits has been discussed.
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17
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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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18
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Pu S, Li Y, Liu Q, Zhang X, Chen L, Li R, Zhang J, Wu T, Tang Q, Yang X, Zhang Z, Huang Y, Kuang J, Li H, Zou M, Jiang W, He J. Inhibition of 5-Lipoxygenase in Hepatic Stellate Cells Alleviates Liver Fibrosis. Front Pharmacol 2021; 12:628583. [PMID: 33679410 PMCID: PMC7930623 DOI: 10.3389/fphar.2021.628583] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Accepted: 01/15/2021] [Indexed: 02/05/2023] Open
Abstract
Background and Purpose: Activation of hepatic stellate cells (HSC) is a central driver of liver fibrosis. 5-lipoxygenase (5-LO) is the key enzyme that catalyzes arachidonic acid into leukotrienes. In this study, we examined the role of 5-LO in HSC activation and liver fibrosis. Main Methods: Culture medium was collected from quiescent and activated HSC for target metabolomics analysis. Exogenous leukotrienes were added to culture medium to explore their effect in activating HSC. Genetic ablation of 5-LO in mice was used to study its role in liver fibrosis induced by CCl4 and a methionine-choline-deficient (MCD) diet. Pharmacological inhibition of 5-LO in HSC was used to explore the effect of this enzyme in HSC activation and liver fibrosis. Key Results: The secretion of LTB4 and LTC4 was increased in activated vs. quiescent HSC. LTB4 and LTC4 contributed to HSC activation by activating the extracellular signal-regulated protein kinase pathway. The expression of 5-LO was increased in activated HSC and fibrotic livers of mice. Ablation of 5-LO in primary HSC inhibited both mRNA and protein expression of fibrotic genes. In vivo, ablation of 5-LO markedly ameliorated the CCl4- and MCD diet-induced liver fibrosis and liver injury. Pharmacological inhibition of 5-LO in HSC by targeted delivery of the 5-LO inhibitor zileuton suppressed HSC activation and improved CCl4- and MCD diet-induced hepatic fibrosis and liver injury. Finally, we found increased 5-LO expression in patients with non-alcoholic steatohepatitis and liver fibrosis. Conclusion: 5-LO may play a critical role in activating HSC; genetic ablation or pharmacological inhibition of 5-LO improved CCl4-and MCD diet-induced liver fibrosis.
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Affiliation(s)
- Shiyun Pu
- Department of Pharmacy and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.,Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital, Sichuan University, Chengdu, China
| | - Yanping Li
- Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital, Sichuan University, Chengdu, China
| | - Qinhui Liu
- Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital, Sichuan University, Chengdu, China
| | - Xu Zhang
- Tianjin Key Laboratory of Metabolic Diseases and Department of Physiology, Tianjin Medical University, Tianjin, China
| | - Lei Chen
- Department of Pharmacy and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.,Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital, Sichuan University, Chengdu, China
| | - Rui Li
- Department of Pharmacy and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.,Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital, Sichuan University, Chengdu, China
| | - Jinhang Zhang
- Department of Pharmacy and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.,Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital, Sichuan University, Chengdu, China
| | - Tong Wu
- Department of Pharmacy and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.,Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital, Sichuan University, Chengdu, China
| | - Qin Tang
- Department of Pharmacy and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.,Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital, Sichuan University, Chengdu, China
| | - Xuping Yang
- Department of Pharmacy and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.,Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital, Sichuan University, Chengdu, China
| | - Zijing Zhang
- Department of Pharmacy and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.,Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital, Sichuan University, Chengdu, China
| | - Ya Huang
- Department of Pharmacy and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.,Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital, Sichuan University, Chengdu, China
| | - Jiangying Kuang
- Department of Pharmacy and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.,Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital, Sichuan University, Chengdu, China
| | - Hong Li
- Department of Pharmacy and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.,Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital, Sichuan University, Chengdu, China
| | - Min Zou
- Department of Pharmacy and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Wei Jiang
- Molecular Medicine Research Center, West China Hospital of Sichuan University, Chengdu, China
| | - Jinhan He
- Department of Pharmacy and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.,Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital, Sichuan University, Chengdu, China
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19
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Zhang J, Hodges A, Chen SH, Pan PY. Myeloid-derived suppressor cells as cellular immunotherapy in transplantation and autoimmune diseases. Cell Immunol 2021; 362:104300. [PMID: 33582607 DOI: 10.1016/j.cellimm.2021.104300] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Revised: 01/25/2021] [Accepted: 01/26/2021] [Indexed: 12/15/2022]
Abstract
Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells, which have been characterized for their immunosuppressive capacity through multiple mechanisms. These cells have been extensively studied in the field of tumor immunity. Emerging evidence has highlighted its essential role in maintaining immune tolerance in transplantation and autoimmunity. Because of their robust immune inhibitory activities, there has been growing interest in MDSC-based cellular therapy. Various pre-clinical studies have demonstrated that the adoptive transfer of MDCS represented a promising therapeutic strategy for immune-related disorders. In this review, we summarize relevant studies of MDSC-based cell therapy in transplantation and autoimmune diseases and discuss the challenges and future directions for clinical application of MDSC-based cell therapy.
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Affiliation(s)
- Jilu Zhang
- Center for Immunotherapy Research, Cancer Center of Excellence, Houston Methodist Research Institute, Houston, TX, United States.
| | - Alan Hodges
- Center for Immunotherapy Research, Cancer Center of Excellence, Houston Methodist Research Institute, Houston, TX, United States; Texas A&M College of Medicine, Bryan, TX, United States
| | - Shu-Hsia Chen
- Center for Immunotherapy Research, Cancer Center of Excellence, Houston Methodist Research Institute, Houston, TX, United States; Texas A&M College of Medicine, Bryan, TX, United States
| | - Ping-Ying Pan
- Center for Immunotherapy Research, Cancer Center of Excellence, Houston Methodist Research Institute, Houston, TX, United States; Texas A&M College of Medicine, Bryan, TX, United States.
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20
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Chen Y, Qian B, Sun X, Kang Z, Huang Z, Ding Z, Dong L, Chen J, Zhang J, Zang Y. Sox9/INHBB axis-mediated crosstalk between the hepatoma and hepatic stellate cells promotes the metastasis of hepatocellular carcinoma. Cancer Lett 2020; 499:243-254. [PMID: 33246092 DOI: 10.1016/j.canlet.2020.11.025] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Revised: 10/06/2020] [Accepted: 11/18/2020] [Indexed: 02/08/2023]
Abstract
The activation of hepatic stellate cells (HSCs) and liver fibrosis in the peri-tumoral tissue contributes to the progression of hepatocellular carcinoma (HCC). However, the mechanisms underlying the crosstalk between hepatoma and peri-tumoral HSCs remain elusive. We found that the Sox9/INHBB axis is upregulated in HCC and is associated with tumor metastasis. Using gain- and loss-of-function approaches, we revealed that the Sox9/INHBB axis promotes the growth and metastasis of an orthotopic HCC tumor by activating the peri-tumoral HSCs. Mechanistically, Sox9 induces INHBB expression by directly binding to its enhancer, thus aiding in the secretion of activin B from hepatoma cells, and in turn, promoting the activation of the surrounding HSCs through activin B/Smad signaling. Furthermore, inhibition of activin B/Smad singaling attenuates the fibrotic response in the peri-tumoral tissue and decreases the incidence of metastasis. Finally, clinical analyses indicated a positive correlation between Sox9 and INHBB expression in HCC specimens and identified the Sox9/INHBB axis as a positive regulator of liver fibrosis. In conclusion, Sox9/INHBB axis-mediated crosstalk between hepatoma cells and HSCs induces a fertile environment favoring HCC metastasis, thereby exhibiting as a potential therapeutic target.
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Affiliation(s)
- Yu Chen
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Science, Nanjing University, Nanjing, 210093, PR China
| | - Baowei Qian
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Science, Nanjing University, Nanjing, 210093, PR China
| | - Xiaolin Sun
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Science, Nanjing University, Nanjing, 210093, PR China
| | - Zhiqian Kang
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Science, Nanjing University, Nanjing, 210093, PR China
| | - Zhen Huang
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Science, Nanjing University, Nanjing, 210093, PR China
| | - Zhi Ding
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Science, Nanjing University, Nanjing, 210093, PR China
| | - Lei Dong
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Science, Nanjing University, Nanjing, 210093, PR China
| | - Jiangning Chen
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Science, Nanjing University, Nanjing, 210093, PR China; State Key Laboratory of Analytical Chemistry for Life Sciences and Collaborative Innovation Center of Chemistry for Life Sciences, Nanjing, 210093, PR China
| | - Junfeng Zhang
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Science, Nanjing University, Nanjing, 210093, PR China.
| | - Yuhui Zang
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Science, Nanjing University, Nanjing, 210093, PR China.
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21
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Gao Y, Xu H, Li N, Wang H, Ma L, Chen S, Liu J, Zheng Y, Zhang Y. Renal cancer-derived exosomes induce tumor immune tolerance by MDSCs-mediated antigen-specific immunosuppression. Cell Commun Signal 2020; 18:106. [PMID: 32641056 PMCID: PMC7341585 DOI: 10.1186/s12964-020-00611-z] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Accepted: 06/08/2020] [Indexed: 12/15/2022] Open
Abstract
Backgound Although Myeloid-derived suppressor cells (MDSCs) have a prominent ability to suppress the immune responses of T lymphocytes and propel tumor immune escape, a lack of profound systemic immunesuppression in tumor-bearing mice and tumor patients. The underlying mechanism of these remains unclear. Methods For this purpose, renal cancer-derived exosomes (RDEs) were first labeled with PKH67 and been observed the internalization by MDSCs. Flow cytometry analysis showed the proportion and activity change of MDSCs in spleen and bone marrow induced by RDEs. Further, western blot experiments were used to verify triggered mechanism of MDSCs by RDEs. Finally, proliferation and cytotoxicity of cytotoxic T lymphocytes (CTLs) co-cultured with MDSCs in vitro and a series of experiments in vivo were performed to demonstrate the specific inhibitory effect of RDEs-induced MDSCs. Results This study suggested that RDEs crucially contributed to presenting antigenic information, activating and driving specific immunosuppressive effect to MDSCs. HSP70, which is highly expressed in RDEs, initiate this process in a toll like receptor 2 (TLR2)-dependent manner. Importantly, RDEs-induced MDSCs could exert an antigen-specific immunosuppression effect on CTL and specific promote renal tumors-growth and immune escape in consequence. Conclusion The immunosuppression mediated by MDSCs which is induced by RDEs is antigen-specific. HSP70, which is highly expressed in RDEs, plays a pivotal role in this process. Targeted abrogating the function of MDSCs, or eliminating the expression of HSP70 in exosomes, or blocking the crosstalk between them provides a new direction and theoretical support for future immunotherapy.
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