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Zhang C, Sui Y, Liu S, Yang M. The Roles of Myeloid-Derived Suppressor Cells in Liver Disease. Biomedicines 2024; 12:299. [PMID: 38397901 PMCID: PMC10886773 DOI: 10.3390/biomedicines12020299] [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: 11/30/2023] [Revised: 01/21/2024] [Accepted: 01/24/2024] [Indexed: 02/25/2024] Open
Abstract
Liver disease-related mortality is a major cause of death worldwide. Hepatic innate and adaptive immune cells play diverse roles in liver homeostasis and disease. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells. MDSCs can be broadly divided into monocytic MDSCs and polymorphonuclear or granulocytic MDSCs, and they functionally interact with both liver parenchymal and nonparenchymal cells, such as hepatocytes and regulatory T cells, to impact liver disease progression. The infiltration and activation of MDSCs in liver disease can be regulated by inflammatory chemokines and cytokines, tumor-associated fibroblasts, epigenetic regulation factors, and gut microbiota during liver injury and cancer. Given the pivotal roles of MDSCs in advanced liver diseases, they can be targeted to treat primary and metastatic liver cancer, liver generation, alcoholic and nonalcoholic liver disease, and autoimmune hepatitis. Currently, several treatments such as the antioxidant and anti-inflammatory agent berberine are under preclinical and clinical investigation to evaluate their therapeutic efficacy on liver disease and their effect on MDSC infiltration and function. Phenotypic alteration of MDSCs in different liver diseases that are in a model-dependent manner and lack special markers for distinct MDSCs are challenges for targeting MDSCs to treat liver disease. Multi-omics study is an option to uncover the features of disease-specific MDSCs and potential gene or protein targets for liver disease treatment. In summary, MDSCs play important roles in the pathogenesis and progression of liver disease by regulating both intrahepatic innate and adaptive immune responses.
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Affiliation(s)
- Chunye Zhang
- Christopher S. Bond Life Sciences Center, University of Missouri, Columbia, MO 65212, USA;
| | - Yuxiang Sui
- School of Life Science, Shanxi Normal University, Linfen 041004, China
| | - Shuai Liu
- The First Affiliated Hospital, Zhejiang University, Hangzhou 310006, China
| | - Ming Yang
- Department of Surgery, University of Missouri, Columbia, MO 65212, USA
- NextGen Precision Health Institute, University of Missouri, Columbia, MO 65212, USA
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Tamadaho RSE, Ritter M, Wiszniewsky A, Arndts K, Mack M, Hoerauf A, Layland LE. Infection-Derived Monocytic MDSCs Require TGF-β to Suppress Filarial-Specific IFN-γ But Not IL-13 Release by Filarial-Specific CD4+ T Cells In Vitro. FRONTIERS IN TROPICAL DISEASES 2022. [DOI: 10.3389/fitd.2021.707100] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Lymphatic filariasis (LF) remains a major health problem with severe economic repercussions in endemic communities of Sub-saharan Africa, South-East Asia and South America. The rodent-specific nematode Litomosoides sigmodontis (Ls) is used to study the immunomodulatory potential of filariae and research has elucidated pathways involving regulatory T cells (Tregs), IL-10 producing cells and alternatively activated macrophages (AAMs) and that CD4+ T cells play a paramount role during infection. Myeloid-derived suppressor cells (MDSCs) have been identified and characterised in man in cancer and other pathologies. The hallmark of MDSC populations is the suppression of T and B cell responses using various mechanisms, which are mostly specific to the pathology or setting. However, until now, it remains unclear whether they play a role in filarial-specific responses. We report here that monocytic MDSCs (Mo-MDSCs, CD11b+Ly6C+Ly6G-) and polymorphonuclear MDSCs (PMN-MDSCs, CD11b+Ly6Cint/loLy6G+) expanded in the thoracic cavity (TC, the site of infection) and correlated positively with filarial life-stages in Ls-infected BALB/c mice. In vitro, only infection-derived Mo-MDSCs showed a suppressive nature by preventing IL-13 and IFN-γ secretion from filarial-specific CD4+ T cells upon co-culture with soluble worm extract. This suppression was not mediated by IL-10, IL-6 or TNF-α, and did not require cell-contact, nitric oxide (NO), IL-4/IL-5 signalling pathways or CCR2. Interestingly, neutralizing TGF-β significantly rescued IFN-γ but not IL-13 production by filarial-specific CD4+ T cells. In comparison to naive cells, PCR array data showed an overall down-regulation of inflammatory pathways in both infection-derived Mo-MDSCs and PMN-MDSCs. In conclusion, these primary data sets show activity and expansion of MDSCs during Ls infection adding this regulatory cell type to the complex milieu of host responses during chronic helminth infections.
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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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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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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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Tamadaho RSE, Hoerauf A, Layland LE. Immunomodulatory effects of myeloid-derived suppressor cells in diseases: Role in cancer and infections. Immunobiology 2017; 223:432-442. [PMID: 29246400 DOI: 10.1016/j.imbio.2017.07.001] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2016] [Revised: 06/05/2017] [Accepted: 07/02/2017] [Indexed: 01/05/2023]
Abstract
Myeloid-derived suppressor cells (MDSCs) are heterogeneous cells capable of abrogating T and B cells responses and have been identified in numerous cancers. As with other regulatory cell populations, they aim to maintain balance between host-defence-associated inflammation and ensuing tissue pathology. MDSC accumulation and/or activation involve several growth factors and cytokines including Granulocyte Macrophage-Colony Stimulating Factor (GM-CSF) and Interleukin (IL)-6 and suppression has been linked to receptors such as IL-4Rα. Other immune pathways, such as Toll-like receptors (TLRs) have also been shown to interfere in MDSC activity adding to the complexity in clarifying their pathways. Monocytic- (Mo-MDSCs) and polymorphonuclear- (PMN-MDSCs) cells are two subsets of MDSCs that have been well characterized and have been shown to function through different mechanisms although both appear to require nitric oxide. In human and murine model settings, MDSCs have been shown to have inhibitory effects on T cell responses during bacterial, parasitic and viral pathologies and an increase of MDSC numbers has been associated with pathological conditions. Interestingly, the environment impacts on MDSC activity and regulatory T cells (Tregs), mast cells and a few cells that may help MDSC in order to regulate immune responses. Since the majority of pioneering data on MDSCs has stemmed from research on malignancies, this review will summarize MDSC biology and function in cancer and highlight current knowledge about these cells during infectious pathologies as well.
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Affiliation(s)
- Ruth S E Tamadaho
- Institute of Medical Microbiology, Immunology and Parasitology (IMMIP), University Hospital of Bonn, Sigmund-Freud-Str. 25, 53127 Bonn, Germany
| | - Achim Hoerauf
- Institute of Medical Microbiology, Immunology and Parasitology (IMMIP), University Hospital of Bonn, Sigmund-Freud-Str. 25, 53127 Bonn, Germany; German Centre for Infection Research (DZIF), Partner Site, Bonn-Cologne, Bonn, Germany
| | - Laura E Layland
- Institute of Medical Microbiology, Immunology and Parasitology (IMMIP), University Hospital of Bonn, Sigmund-Freud-Str. 25, 53127 Bonn, Germany; German Centre for Infection Research (DZIF), Partner Site, Bonn-Cologne, Bonn, Germany.
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7
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Zhang H, Li Z, Wang L, Tian G, Tian J, Yang Z, Cao G, Zhou H, Zhao L, Wu Z, Yin Z. Critical Role of Myeloid-Derived Suppressor Cells in Tumor-Induced Liver Immune Suppression through Inhibition of NKT Cell Function. Front Immunol 2017; 8:129. [PMID: 28243237 PMCID: PMC5303828 DOI: 10.3389/fimmu.2017.00129] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2016] [Accepted: 01/25/2017] [Indexed: 12/27/2022] Open
Abstract
Metastasis followed by the tumor development is the primary cause of death for cancer patients. However, the underlying molecular mechanisms of how the growth of tumor resulted in the immune suppression, especially at the blood-enriched organ such as liver, were largely unknown. In this report, we studied the liver immune response of tumor-bearing (TB) mice using concanavalin A (Con A)-induced hepatitis model. We demonstrated that TB mice displayed an immune suppression phenotype, with attenuated alanine aminotransferase levels and liver damage upon Con A treatment. We also elucidated that large amounts of myeloid-derived suppressor cells (MDSCs) being influx into the liver in TB mice and these MDSCs were essential for liver immune suppression through both depletion and reconstitution approaches. We further determined that these MDSCs selectively suppressed the IFN-γ production deriving from NKT cells through membrane-bound transforming growth factor β (TGF-β). Finally, we defined a tumor-derived TGF-β-triggered CXCL1/2/5- and CXCR2-dependent recruitment of MDSC into the liver. In summary, our results defined a novel mechanism of liver immune suppression triggered by growing living tumor and provided possible therapeutic targets against these MDSCs.
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Affiliation(s)
- Hongru Zhang
- State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University , Tianjin , China
| | - Zheng Li
- State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin, China; Shenzhou Space Biotechnology Group, Beijing, China
| | - Li Wang
- State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University , Tianjin , China
| | - Gaofei Tian
- State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University , Tianjin , China
| | - Jun Tian
- State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University , Tianjin , China
| | - Zishan Yang
- State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University , Tianjin , China
| | - Guangchao Cao
- The First Affiliate Hospital, Biomedical Translational Research Institute, Guangdong Province Key Laboratory of Molecular Immunology and Antibody Engineering, Jinan University , Guangzhou , China
| | - Hong Zhou
- Department of Immunology, Nanjing Medical University , Nanjing , China
| | - Liqing Zhao
- State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University , Tianjin , China
| | - Zhenzhou Wu
- State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University , Tianjin , China
| | - Zhinan Yin
- State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin, China; The First Affiliate Hospital, Biomedical Translational Research Institute, Guangdong Province Key Laboratory of Molecular Immunology and Antibody Engineering, Jinan University, Guangzhou, China; Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu, Sichuan, China
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8
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O'Connor MA, Rastad JL, Green WR. The Role of Myeloid-Derived Suppressor Cells in Viral Infection. Viral Immunol 2017; 30:82-97. [PMID: 28051364 DOI: 10.1089/vim.2016.0125] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Myeloid-derived suppressor cells (MDSCs) are heterogeneous immature myeloid cells that are well described as potent immune regulatory cells during human cancer and murine tumor models. Reports of MDSCs during viral infections remain limited, and their association with immunomodulation of viral diseases is still being defined. Here, we provide an overview of MDSCs or MDSC-like cells identified during viral infections, including murine viral models and human viral diseases. Understanding the similarities and/or differences of virally induced versus tumor-derived MDSCs will be important for designing future immunotherapeutic approaches.
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Affiliation(s)
- Megan A O'Connor
- 1 Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth , Lebanon , New Hampshire
| | - Jessica L Rastad
- 1 Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth , Lebanon , New Hampshire
| | - William R Green
- 1 Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth , Lebanon , New Hampshire.,2 Norris Cotton Cancer Center , Geisel School of Medicine at Dartmouth, Lebanon , New Hampshire
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9
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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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10
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Demetris AJ, Bellamy COC, Gandhi CR, Prost S, Nakanuma Y, Stolz DB. Functional Immune Anatomy of the Liver-As an Allograft. Am J Transplant 2016; 16:1653-80. [PMID: 26848550 DOI: 10.1111/ajt.13749] [Citation(s) in RCA: 75] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2015] [Revised: 01/26/2016] [Accepted: 01/28/2016] [Indexed: 01/25/2023]
Abstract
The liver is an immunoregulatory organ in which a tolerogenic microenvironment mitigates the relative "strength" of local immune responses. Paradoxically, necro-inflammatory diseases create the need for most liver transplants. Treatment of hepatitis B virus, hepatitis C virus, and acute T cell-mediated rejection have redirected focus on long-term allograft structural integrity. Understanding of insults should enable decades of morbidity-free survival after liver replacement because of these tolerogenic properties. Studies of long-term survivors show low-grade chronic inflammatory, fibrotic, and microvascular lesions, likely related to some combination of environment insults (i.e. abnormal physiology), donor-specific antibodies, and T cell-mediated immunity. The resultant conundrum is familiar in transplantation: adequate immunosuppression produces chronic toxicities, while lightened immunosuppression leads to sensitization, immunological injury, and structural deterioration. The "balance" is more favorable for liver than other solid organ allografts. This occurs because of unique hepatic immune physiology and provides unintended benefits for allografts by modulating various afferent and efferent limbs of allogenic immune responses. This review is intended to provide a better understanding of liver immune microanatomy and physiology and thereby (a) the potential structural consequences of low-level, including allo-antibody-mediated injury; and (b) how liver allografts modulate immune reactions. Special attention is given to the microvasculature and hepatic mononuclear phagocytic system.
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Affiliation(s)
- A J Demetris
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA
| | - C O C Bellamy
- Department of Pathology, University of Edinburgh, Edinburgh, Scotland, UK
| | - C R Gandhi
- Department of Pediatrics, Cincinnati Children's Hospital Medical Center and Department of Surgery, University of Cincinnati, Cincinnati, OH
| | - S Prost
- Department of Pathology, University of Edinburgh, Edinburgh, Scotland, UK
| | - Y Nakanuma
- Department of Diagnostic Pathology, Shizuoka Cancer Center, Shizuoka, Japan
| | - D B Stolz
- Center for Biologic Imaging, Cell Biology, University of Pittsburgh, Pittsburgh, PA
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IL-1RT1 signaling antagonizes IL-11 induced STAT3 dependent cardiac and antral stomach tumor development through myeloid cell enrichment. Oncotarget 2015; 6:679-95. [PMID: 25528766 PMCID: PMC4359248 DOI: 10.18632/oncotarget.2707] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2014] [Accepted: 11/08/2014] [Indexed: 01/04/2023] Open
Abstract
IL-1 is key driver of gastric tumorigenesis and is a downstream target of IL-11 signaling. Recently, IL-1 cytokines, particularly IL-1β, have been flagged as therapeutic targets for gastric cancer treatment. Here, we assess the requirement for IL-1 signaling in gastric tumorigenesis. gp130757FF xIL-1RT1-/- mice were generated to determine the pathological consequence of ablated IL-1 signaling in the IL-11 dependent gp130757FF mouse model of gastric tumorigenesis. Gastric lesions in gp130757FF xIL-1RT1-/- mice were increased in incidence and size compared to gp130757FF mice. Proximal gastric lesions originated from the cardiac region and were associated with elevated STAT3 activation, loss of specialized gastric cells and a modulated immune response including increased expression of TNF-α and MDSC associated genes. Administration of IL-11 to IL-1RT1-/- mice showed similar changes to gp130757FF xIL-1RT1-/- mice. Spleens from IL-11 treated wildtype mice showed an enrichment of MDSC and gp130757FF xIL-1RT1-/- mice had increased MDSCs in the stomach compared to gp130757FF mice. Furthermore, crossing TNF-α-/- to gp130757FF mice resulted in reduced lesion size. We conclude that IL-1 signaling antagonizes IL-11/STAT3 mediated pathology and the genetic deletion of IL-1RT1 results in increased tumor burden. We provide evidence that a likely mechanism is due to IL-11/STAT3 dependent enrichment of MDSCs.
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O'Connor MA, Fu WW, Green KA, Green WR. Subpopulations of M-MDSCs from mice infected by an immunodeficiency-causing retrovirus and their differential suppression of T- vs B-cell responses. Virology 2015; 485:263-73. [PMID: 26318248 DOI: 10.1016/j.virol.2015.07.020] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2015] [Revised: 07/27/2015] [Accepted: 07/31/2015] [Indexed: 01/05/2023]
Abstract
Monocytic (CD11b(+)Ly6G(±/Lo)Ly6C(+)) myeloid derived suppressor cells (M-MDSCs) expand following murine retroviral LP-BM5 infection and suppress ex vivo polyclonal T-cell and B-cell responses. M-MDSCs 3 weeks post LP-BM5 infection have decreased suppression of T-cell, but not B-cell, responses and alterations in the degree of iNOS/NO dependence of suppression. M-MDSCs from LP-BM5 infected mice were sorted into four quadrant populations (Ly6C/CD11b density): all quadrants suppressed B-cell responses, but only M-MDSCs expressing the highest levels of Ly6C and CD11b (Q2) significantly suppressed T-cell responses. Further subdivision of this Q2 population revealed the Ly6C(+/Hi) M-MDSC subpopulation as the most suppressive, inhibiting T- and B-cell responses in a full, or partially, iNOS/NO-dependent manner, respectively. In contrast, the lower/moderate levels of suppression by the Ly6C(+/Lo) and Ly6C(+/Mid) M-MDSC Q2 subpopulations, whether versus T- and/or B-cells, displayed little/no iNOS dependency for suppression. These results highlight differential phenotypic and functional immunosuppressive M-MDSC subsets in a retroviral immunodeficiency model.
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Affiliation(s)
- Megan A O'Connor
- Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA
| | - Whitney W Fu
- Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA
| | - Kathy A Green
- Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA
| | - William R Green
- Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA; Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA.
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13
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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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