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Li C, Gao X, Liu Y, Yang B, Dai H, Zhao H, Li Y. The role of natural killer T cells in sepsis-associated acute kidney injury. Int Immunopharmacol 2025; 159:114953. [PMID: 40418883 DOI: 10.1016/j.intimp.2025.114953] [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: 01/31/2025] [Revised: 05/12/2025] [Accepted: 05/21/2025] [Indexed: 05/28/2025]
Abstract
The condition of sepsis, defined by the misregulation of the body's defensive mechanisms against infection, culminates in the potential for catastrophic organ damage and stands as a primary driver of mortality in Intensive Care Units (ICU) settings. Among patients in a critical condition, sepsis is a predominant factor in the development of acute kidney injury (AKI), and the death rate among those with both sepsis and AKI is considerably higher, underscoring the importance of addressing this health crisis. Sepsis-associated acute kidney injury (S-AKI) is a complex process involving inflammation, microcirculatory issues, and metabolic disorders. Among these, the inflammatory response has become a focal point of interest. Bridging the innate and adaptive immunity, natural killer T (NKT) cells can be rapidly activated in sepsis, contributing to sepsis-associated injury and downstream activation of inflammatory cells through the emission of Th1 or Th2 cytokines. They also contribute to S-AKI through the TNF-α/FasL and perforin pathways. Alpha-Galactosylceramide (α-GalCer), acting as a powerful activator for type I NKT (iNKT) cells, is able to regulate the secretory profile of iNKT cells, responding to the pro-inflammatory response and immunosuppressive profiles of sepsis. This review examines the part played by NKT cells in S-AKI and whether α-Galcer could function as a significant regulator in sepsis, based on studies of regression-related mechanisms.
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Affiliation(s)
- Cheng Li
- Department of Intensive Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, Hubei, China; Department of Emergency, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, Hubei, China
| | - Xiaopo Gao
- Department of Intensive Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, Hubei, China; Department of Emergency, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, Hubei, China
| | - Yuan Liu
- Jiangxi Medical College, Nanchang University, Nanchang 330000, Jiangxi, China
| | - Bin Yang
- Department of Intensive Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, Hubei, China; Department of Emergency, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, Hubei, China
| | - Hongkai Dai
- Department of Intensive Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, Hubei, China; Department of Emergency, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, Hubei, China
| | - Hui Zhao
- Department of Intensive Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, Hubei, China; Department of Emergency, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, Hubei, China
| | - Yongshen Li
- Department of Intensive Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, Hubei, China; Department of Emergency, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, Hubei, China.
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Yagi H, Boeck M, Neilsen K, Yang J, Ko M, Tomita Y, Negishi K, Fu Z, Sun Y, Smith LE. Choroidal Neovascularization Is Suppressed With Activation of TREM2 in Mononuclear Phagocytes-Brief Report. Arterioscler Thromb Vasc Biol 2025; 45:769-777. [PMID: 40143815 PMCID: PMC12017599 DOI: 10.1161/atvbaha.124.321809] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Accepted: 03/10/2025] [Indexed: 03/28/2025]
Abstract
BACKGROUND Mononuclear phagocytes contribute to pathological angiogenesis in age-related macular degeneration, a leading worldwide cause of visual impairment. However, the mechanisms that orchestrate the functions of mononuclear phagocytes remain poorly understood. TREM2 (triggering receptor on myeloid cells 2) has been shown to be crucial for the activation of mononuclear phagocytes in atherosclerosis, fatty liver disease, and Alzheimer disease. The objective of this study was to investigate the role of TREM2 in pathological angiogenesis in age-related macular degeneration. METHODS C57BL/6J and Trem2 knockout mice were subjected to laser-induced choroidal neovascularization, a model of choroidal neovascular age-related macular degeneration. Purified bovine sulfatide and agonist anti-TREM2 antibody was used to activate TREM2 signaling. The expression of TREM2 or downstream signals were assessed with immunohistochemistry or real-time quantitative PCR. In vitro murine macrophage RAW264.7 cells were used to investigate the direct impact of sulfatide on inflammatory and phagocytic responses. RESULTS We found that pharmacological activation of TREM2 suppressed laser-induced choroidal neovessel formation. The activation of TREM2 in mononuclear phagocytes suppressed TNF (tumor necrosis factor) and subsequently promoted phagocytosis. CONCLUSIONS These findings demonstrate that activation of TREM2 in mononuclear phagocytes suppresses the proinflammatory response, promotes phagocytosis, and impedes choroidal neovessel formation. Our study provides insight into the critical role of TREM2 in pathological angiogenesis.
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Affiliation(s)
- Hitomi Yagi
- Department of Ophthalmology, Boston Children’s Hospital, Harvard Medical School, MA (H.Y., M.B., K. Neilsen, J.Y., M.K., Y.T., Z.F., Y.S., L.E.H.S.)
- Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan (H.Y., Y.T., K. Negishi)
| | - Myriam Boeck
- Department of Ophthalmology, Boston Children’s Hospital, Harvard Medical School, MA (H.Y., M.B., K. Neilsen, J.Y., M.K., Y.T., Z.F., Y.S., L.E.H.S.)
- Eye Center, Medical Center, Faculty of Medicine, University of Freiburg, Germany (M.B.)
| | - Katherine Neilsen
- Department of Ophthalmology, Boston Children’s Hospital, Harvard Medical School, MA (H.Y., M.B., K. Neilsen, J.Y., M.K., Y.T., Z.F., Y.S., L.E.H.S.)
| | - Jay Yang
- Department of Ophthalmology, Boston Children’s Hospital, Harvard Medical School, MA (H.Y., M.B., K. Neilsen, J.Y., M.K., Y.T., Z.F., Y.S., L.E.H.S.)
| | - Minji Ko
- Department of Ophthalmology, Boston Children’s Hospital, Harvard Medical School, MA (H.Y., M.B., K. Neilsen, J.Y., M.K., Y.T., Z.F., Y.S., L.E.H.S.)
| | - Yohei Tomita
- Department of Ophthalmology, Boston Children’s Hospital, Harvard Medical School, MA (H.Y., M.B., K. Neilsen, J.Y., M.K., Y.T., Z.F., Y.S., L.E.H.S.)
- Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan (H.Y., Y.T., K. Negishi)
| | - Kazuno Negishi
- Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan (H.Y., Y.T., K. Negishi)
| | - Zhongjie Fu
- Department of Ophthalmology, Boston Children’s Hospital, Harvard Medical School, MA (H.Y., M.B., K. Neilsen, J.Y., M.K., Y.T., Z.F., Y.S., L.E.H.S.)
| | - Ye Sun
- Department of Ophthalmology, Boston Children’s Hospital, Harvard Medical School, MA (H.Y., M.B., K. Neilsen, J.Y., M.K., Y.T., Z.F., Y.S., L.E.H.S.)
| | - Lois E.H. Smith
- Department of Ophthalmology, Boston Children’s Hospital, Harvard Medical School, MA (H.Y., M.B., K. Neilsen, J.Y., M.K., Y.T., Z.F., Y.S., L.E.H.S.)
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Dhayanithy G, Radhakrishnan S, Ann Martin C, Caroline Martin J, Hakeem AR, Jothimani D, Kalkura SN, Rela M. Understanding immunological insights of liver transplantation: a practice for attaining operational tolerance. Clin Exp Immunol 2025; 219:uxae125. [PMID: 39973343 PMCID: PMC11878573 DOI: 10.1093/cei/uxae125] [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: 04/17/2024] [Revised: 11/15/2024] [Accepted: 02/19/2025] [Indexed: 02/21/2025] Open
Abstract
Liver transplantation has been at the forefront of medical research, with efforts concentrated on understanding the intricate cellular and molecular dynamics involved this complex procedure. This body of work has chronicled critical clinical advancements, identified challenges, and highlighted progressive improvements in surgical practices. These concerted efforts have significantly contributed to the evolution and enhancement of liver transplantation, elevating it to its current level of sophistication. A successful liver transplant now demands an integrated, multidisciplinary approach that includes not only expanding the donor pool from deceased to living donors but also embracing advances in surgical methods, efficiently managing post-transplant complications, and, importantly, achieving operational tolerance. The latter, operational tolerance, is a state wherein the recipient's immune system is coaxed into accepting the transplanted organ without the long-term use of immunosuppressive drugs, thereby minimizing potential side effects, and improving quality of life. Understanding the critical immune mechanisms that aim to prevent graft rejection is essential from an immunological perspective. This review aims to highlight the crucial areas of host versus graft immune responses, making a clear distinction between organs received from living and deceased donors. It examines how these immune responses, both innate and adaptive, are initiated and proposes the exploration of molecular docking sites as a strategy to curb unwanted immune reactions. Additionally, this review explores the promising potential of biomarkers in predicting graft rejection, and emphasizes the importance of achieving tolerance and the continuous quest for innovative strategies to enhance the success and longevity of liver transplants.
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Affiliation(s)
| | | | | | - Josette Caroline Martin
- Department of Pathology, Sri Venkateshwara Medical College Hospital and Research Institute, Pondicherry, India
| | | | - Dinesh Jothimani
- Dr. Rela Institute and Medical Centre, Chromepet, Chennai, India
| | - Subbaraya Narayana Kalkura
- Crystal Growth Centre, Anna University, Guindy, Chennai, India
- National Foundation for Liver Research, Chromepet, Chennai, India
| | - Mohamed Rela
- National Foundation for Liver Research, Chromepet, Chennai, India
- Dr. Rela Institute and Medical Centre, Chromepet, Chennai, India
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Chen L, Elizalde M, Alvarez-Sola G. The Role of Sulfatides in Liver Health and Disease. FRONT BIOSCI-LANDMRK 2025; 30:25077. [PMID: 39862071 DOI: 10.31083/fbl25077] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2024] [Revised: 07/31/2024] [Accepted: 08/07/2024] [Indexed: 01/27/2025]
Abstract
Sulfatides or 3-O-sulfogalactosylceramide are negatively charged sulfated glycosphingolipids abundant in the brain and kidneys and play crucial roles in nerve impulse conduction and urinary pH regulation. Sulfatides are present in the liver, specifically in the biliary tract. Sulfatides are self-lipid antigens presented by cholangiocytes to activate cluster of differentiation 1d (CD1d)-restricted type II natural killer T (NKT) cells. These cells are involved in alcohol-related liver disease (ArLD) and ischemic liver injury and exert anti-inflammatory effects by regulating the activity of pro-inflammatory type I NKT cells. Loss of sulfatides has been implicated in the chronic inflammatory disorder of the liver known as primary sclerosing cholangitis (PSC); bile ducts deficient in sulfatides increase their permeability, resulting in the spread of bile into the liver parenchyma. Previous studies have shown elevated levels of sulfatides in hepatocellular carcinoma (HCC), where sulfatides could act as adhesive molecules that contribute to cancer metastasis. We have recently demonstrated how loss of function of GAL3ST1, a limiting enzyme involved in sulfatide synthesis, reduces tumorigenic capacity in cholangiocarcinoma (CCA) cells. The biological function of sulfatides in the liver is still unclear; however, this review aims to summarize the existing findings on the topic.
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Affiliation(s)
- Lin Chen
- Department of Surgery, School of Nutrition and Translational Research in Metabolism, Maastricht University, 6200 MD Maastricht, The Netherlands
| | - Montserrat Elizalde
- Division of Gastroenterology-Hepatology, Department of Internal Medicine, Maastricht University, 6200 MD Maastricht, The Netherlands
| | - Gloria Alvarez-Sola
- Department of Surgery, School of Nutrition and Translational Research in Metabolism, Maastricht University, 6200 MD Maastricht, The Netherlands
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Sun J, Xu H, Li B, Deng W, Han X, Zhong X, Zhu J, Jiang Y, Wang Z, Zhang D, Sun G. IFITM1 aggravates ConA-Induced autoimmune hepatitis by promoting NKT cell activation through increased AMPK-Dependent mitochondrial function. Int Immunopharmacol 2025; 144:113692. [PMID: 39602958 DOI: 10.1016/j.intimp.2024.113692] [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: 10/10/2024] [Revised: 11/18/2024] [Accepted: 11/19/2024] [Indexed: 11/29/2024]
Abstract
Although interferon-induced transmembrane 1 (IFITM1) is known for its crucial role in antiviral immunity, its involvement in autoimmune hepatitis (AIH) remains largely unexplored. In this study, we observed that IFITM1 expression is markedly upregulated in a Concanavalin A (ConA)-induced AIH model, with particularly high and markedly elevated expression in natural killer T (NKT) cells. To further understand the role of IFITM1, we examined the responses of IFITM1-/- mice in a model of ConA-induced liver injury. In comparison to wild-type mice, IFITM1-/- mice exhibited reduced sensitivity in this model, as evidenced by significantly ameliorated necrosis areas, lower serum aminotransferase levels, a reduced number of intrahepatic NKT cells, and decreased expression of inflammatory factors, such as IL-1β, IL-6, IFN-γ and TNF-α. Notably, by using IFITM1-GFP mice and IFITM1-/- mice, we demonstrated that IFITM1 expression in NKT cells is crucial for their proliferation, proinflammatory cytokine production, and cytotoxic functions. Furthermore, analysis of single-cell RNA sequencingdata revealed that IFITM1 is essential for mitochondrial function, which is mediated by the AMP-activated protein kinase (AMPK) pathway. We also validated the importance of IFITM1 for the AMPK pathway and mitochondrial ATP synthesis in vivo. Together, our findings elucidate that IFITM1 could regulate NKT cell activation and survival by promoting mitochondrial function during AIH.
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Affiliation(s)
- Jie Sun
- Medical Research Center, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, Beijing 10020, China; Department of Gastroenterology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China
| | - Haozhe Xu
- Medical Research Center, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, Beijing 10020, China; Department of Gastroenterology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China
| | - Buer Li
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Wanqing Deng
- Medical Research Center, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, Beijing 10020, China; Department of Gastroenterology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China
| | - Xiaotong Han
- Medical Research Center, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, Beijing 10020, China; Department of Gastroenterology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China
| | - Xinjie Zhong
- Medical Research Center, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, Beijing 10020, China; Department of Gastroenterology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China
| | - Jingjing Zhu
- Medical Research Center, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, Beijing 10020, China; Department of Gastroenterology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China
| | - Yuan Jiang
- Medical Research Center, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, Beijing 10020, China; Department of Gastroenterology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China
| | - Zeyu Wang
- Medical Research Center, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, Beijing 10020, China; Department of Gastroenterology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China
| | - Dong Zhang
- Medical Research Center, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, Beijing 10020, China; Department of Gastroenterology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China
| | - Guangyong Sun
- Medical Research Center, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, Beijing 10020, China; Department of Gastroenterology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China.
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Kang M, Park HK, Kim KS, Choi D. Animal models for transplant immunology: bridging bench to bedside. CLINICAL TRANSPLANTATION AND RESEARCH 2024; 38:354-376. [PMID: 39233453 PMCID: PMC11732767 DOI: 10.4285/ctr.24.0029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Revised: 07/05/2024] [Accepted: 07/07/2024] [Indexed: 09/06/2024]
Abstract
The progress of transplantation has been propelled forward by animal experiments. Animal models have not only provided opportunities to understand complex immune mechanisms in transplantation but also served as a platform to assess therapeutic interventions. While small animals have been instrumental in uncovering new therapeutic concepts related to immunosuppression and immune tolerance, the progression to human trials has largely been driven by studies in large animals. Recent research has begun to explore the potential of porcine organs to address the shortage of available organs. The consistent progress in transplant immunology research can be attributed to a thorough understanding of animal models. This review provides a comprehensive overview of the available animal models, detailing their modifications, strengths, and weaknesses, as well as their historical applications, to aid researchers in selecting the most suitable model for their specific research needs.
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Affiliation(s)
- Minseok Kang
- Department of Surgery, Hanyang University College of Medicine, Seoul, Korea
| | - Hwon Kyum Park
- Department of Surgery, Hanyang University College of Medicine, Seoul, Korea
| | - Kyeong Sik Kim
- Department of Surgery, Hanyang University College of Medicine, Seoul, Korea
| | - Dongho Choi
- Department of Surgery, Hanyang University College of Medicine, Seoul, Korea
- Hanyang Institute of Bioscience and Biotechnology, Hanyang University, Seoul, Korea
- Research Institute of Regenerative Medicine and Stem Cells, Hanyang University, Seoul, Korea
- Department of HY-KIST Bio-convergence, Hanyang University, Seoul, Korea
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7
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Tamura T, Cheng C, Villaseñor-Altamirano A, Yamada K, Ikeda K, Hayashida K, Menon JA, Chen XD, Chung H, Varon J, Chen J, Choi J, Cullen AM, Guo J, Lin X, Olenchock BA, Pinilla-Vera MA, Manandhar R, Sheikh MDA, Hou PC, Lawler PR, Oldham WM, Seethala RR, Immunology of Cardiac Arrest Network (I-CAN), Baron RM, Bohula EA, Morrow DA, Blumberg RS, Chen F, Merriam LT, Weissman AJ, Brenner MB, Chen X, Ichinose F, Kim EY. Diverse NKT cells regulate early inflammation and neurological outcomes after cardiac arrest and resuscitation. Sci Transl Med 2024; 16:eadq5796. [PMID: 39630883 PMCID: PMC11792709 DOI: 10.1126/scitranslmed.adq5796] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2024] [Accepted: 09/30/2024] [Indexed: 12/07/2024]
Abstract
Neurological injury drives most deaths and morbidity among patients hospitalized for out-of-hospital cardiac arrest (OHCA). Despite its clinical importance, there are no effective pharmacological therapies targeting post-cardiac arrest (CA) neurological injury. Here, we analyzed circulating immune cells from a large cohort of patients with OHCA, finding that lymphopenia independently associated with poor neurological outcomes. Single-cell RNA sequencing of immune cells showed that T cells with features of both innate T cells and natural killer (NK) cells were increased in patients with favorable neurological outcomes. We more specifically identified an early increase in circulating diverse NKT (dNKT) cells in a separate cohort of patients with OHCA who had good neurological outcomes. These cells harbored a diverse T cell receptor repertoire but were consistently specific for sulfatide antigen. In mice, we found that sulfatide-specific dNKT cells trafficked to the brain after CA and resuscitation. In the brains of mice lacking NKT cells (Cd1d-/-), we observed increased inflammatory chemokine and cytokine expression and accumulation of macrophages when compared with wild-type mice. Cd1d-/- mice also had increased neuronal injury, neurological dysfunction, and worse mortality after CA. To therapeutically enhance dNKT cell activity, we treated mice with sulfatide lipid after CA, showing that it improved neurological function. Together, these data show that sulfatide-specific dNKT cells are associated with good neurological outcomes after clinical OHCA and are neuroprotective in mice after CA. Strategies to enhance the number or function of dNKT cells may thus represent a treatment approach for CA.
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Affiliation(s)
- Tomoyoshi Tamura
- Department of Medicine, Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Boston, MA 02115
- Harvard Medical School; Boston, MA 02115
- Department of Emergency and Critical Care Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Changde Cheng
- Department of Computational Biology, St Jude Children’s Research Hospital, Nashville 38105, TN
- Department of Medicine, Division of Hematology and Oncology, Stem Cell Biology Program, University of Alabama at Birmingham, Birmingham 35233, AL
| | - Ana Villaseñor-Altamirano
- Department of Medicine, Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Boston, MA 02115
- Harvard Medical School; Boston, MA 02115
| | - Kohei Yamada
- Department of Medicine, Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Boston, MA 02115
- Harvard Medical School; Boston, MA 02115
| | - Kohei Ikeda
- Harvard Medical School; Boston, MA 02115
- Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston 02114, MA
| | - Kei Hayashida
- Harvard Medical School; Boston, MA 02115
- Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston 02114, MA
| | - Jaivardhan A Menon
- Department of Medicine, Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Boston, MA 02115
- Harvard Medical School; Boston, MA 02115
| | - Xi Dawn Chen
- Broad Institute of Harvard and MIT, Cambridge 02138, MA
- Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA
| | - Hattie Chung
- Broad Institute of Harvard and MIT, Cambridge 02138, MA
- Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA
| | - Jack Varon
- Department of Medicine, Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Boston, MA 02115
- Harvard Medical School; Boston, MA 02115
| | - Jiani Chen
- Department of Computational Biology, St Jude Children’s Research Hospital, Nashville 38105, TN
| | - Jiyoung Choi
- Department of Medicine, Division of Rheumatology, Inflammation and Immunity, Brigham and Women’s Hospital, Boston 02115, MA
| | - Aidan M. Cullen
- Department of Medicine, Division of Rheumatology, Inflammation and Immunity, Brigham and Women’s Hospital, Boston 02115, MA
| | - Jingyu Guo
- Department of Medicine, Division of Rheumatology, Inflammation and Immunity, Brigham and Women’s Hospital, Boston 02115, MA
| | - Xi Lin
- Harvard Medical School; Boston, MA 02115
- Department of Medicine, Division of Gastroenterology, Brigham and Women’s Hospital, Boston, MA 02142, USA
| | - Benjamin A. Olenchock
- Harvard Medical School; Boston, MA 02115
- Department of Medicine, Division of Cardiovascular Division, Brigham and Women’s Hospital, Boston 02115, MA
| | - Mayra A. Pinilla-Vera
- Department of Medicine, Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Boston, MA 02115
| | - Reshmi Manandhar
- Department of Medicine, Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Boston, MA 02115
- Harvard Medical School; Boston, MA 02115
| | - Muhammad Dawood Amir Sheikh
- Department of Medicine, Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Boston, MA 02115
| | - Peter C. Hou
- Harvard Medical School; Boston, MA 02115
- Department of Emergency Medicine, Division of Emergency and Critical Care Medicine, Brigham and Women’s Hospital, Boston 02115, MA
| | - Patrick R. Lawler
- McGill University Health Centre, Montreal, Quebec H3A 2B4, Canada
- University of Toronto, Toronto, Ontario M5R 0A3, Canada
| | - William M. Oldham
- Department of Medicine, Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Boston, MA 02115
- Harvard Medical School; Boston, MA 02115
| | - Raghu R. Seethala
- Harvard Medical School; Boston, MA 02115
- Department of Emergency Medicine, Division of Emergency and Critical Care Medicine, Brigham and Women’s Hospital, Boston 02115, MA
| | | | - Rebecca M. Baron
- Department of Medicine, Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Boston, MA 02115
- Harvard Medical School; Boston, MA 02115
| | - Erin A. Bohula
- Harvard Medical School; Boston, MA 02115
- Department of Medicine, Division of Cardiovascular Division, Brigham and Women’s Hospital, Boston 02115, MA
| | - David A. Morrow
- Harvard Medical School; Boston, MA 02115
- Department of Medicine, Division of Cardiovascular Division, Brigham and Women’s Hospital, Boston 02115, MA
| | - Richard S. Blumberg
- Harvard Medical School; Boston, MA 02115
- Department of Medicine, Division of Gastroenterology, Brigham and Women’s Hospital, Boston, MA 02142, USA
| | - Fei Chen
- Broad Institute of Harvard and MIT, Cambridge 02138, MA
- Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA
| | - Louis T. Merriam
- Department of Medicine, Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Boston, MA 02115
| | - Alexandra J. Weissman
- Department of Emergency Medicine, University of Pittsburgh School of Medicine; Pittsburgh 15261, PA
| | - Michael B. Brenner
- Harvard Medical School; Boston, MA 02115
- Department of Medicine, Division of Rheumatology, Inflammation and Immunity, Brigham and Women’s Hospital, Boston 02115, MA
| | - Xiang Chen
- Department of Computational Biology, St Jude Children’s Research Hospital, Nashville 38105, TN
| | - Fumito Ichinose
- Harvard Medical School; Boston, MA 02115
- Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston 02114, MA
| | - Edy Y. Kim
- Department of Medicine, Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Boston, MA 02115
- Harvard Medical School; Boston, MA 02115
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Calamita E, Liu WH, Ogger PP, Griffin L, Michalaki C, Murphy F, Worrell J, McCarthy C, Agro A, Hertz M, Maher TM, Lloyd CM, Molyneaux P, Kumar V, Byrne AJ. Type 1 Invariant Natural Killer T Cells Drive Lung Fibrosis. Am J Respir Crit Care Med 2024; 210:521-523. [PMID: 38935441 DOI: 10.1164/rccm.202402-0288le] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2024] [Accepted: 06/25/2024] [Indexed: 06/29/2024] Open
Affiliation(s)
- Emily Calamita
- National Heart and Lung Institute, Imperial College London, London, United Kingdom
| | - Wing Han Liu
- National Heart and Lung Institute, Imperial College London, London, United Kingdom
| | - Patricia P Ogger
- National Heart and Lung Institute, Imperial College London, London, United Kingdom
| | - Leia Griffin
- National Heart and Lung Institute, Imperial College London, London, United Kingdom
| | - Christina Michalaki
- National Heart and Lung Institute, Imperial College London, London, United Kingdom
| | - Faye Murphy
- Conway Institute and School of Medicine, University College Dublin, Dublin, Ireland
| | - Julie Worrell
- Conway Institute and School of Medicine, University College Dublin, Dublin, Ireland
| | - Cormac McCarthy
- Conway Institute and School of Medicine, University College Dublin, Dublin, Ireland
| | | | | | - Toby M Maher
- National Heart and Lung Institute, Imperial College London, London, United Kingdom
- Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Clare M Lloyd
- National Heart and Lung Institute, Imperial College London, London, United Kingdom
| | - Philip Molyneaux
- National Heart and Lung Institute, Imperial College London, London, United Kingdom
| | - Vipin Kumar
- Laboratory of Immune Regulation, Department of Medicine, University of California, San Diego, La Jolla, California
- GRI Bio, La Jolla, California; and
| | - Adam J Byrne
- National Heart and Lung Institute, Imperial College London, London, United Kingdom
- Conway Institute and School of Medicine, University College Dublin, Dublin, Ireland
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9
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Zhuang RZ, Zhuo JY, Dong SY, Ling Q, Zhu HK, Xu X. Prognostic value of innate immune cell densities in patients with hepatocellular carcinoma after liver transplantation. Hepatobiliary Pancreat Dis Int 2024:S1499-3872(24)00104-8. [PMID: 39089944 DOI: 10.1016/j.hbpd.2024.07.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2024] [Accepted: 07/15/2024] [Indexed: 08/04/2024]
Affiliation(s)
- Run-Zhou Zhuang
- Department of Thoracic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, 310003, China
| | - Jian-Yong Zhuo
- NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, 310003, China
| | - Si-Yi Dong
- National Center for Healthcare Quality Management of Liver Transplant, Hangzhou 310003, China
| | - Qi Ling
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Heng-Kai Zhu
- Department of Hepatobiliary and Pancreatic Surgery, Department of Liver Transplantation, Shulan (Hangzhou) Hospital, Zhejiang Shuren University School of Medicine, Hangzhou 310022, China
| | - Xiao Xu
- NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, 310003, China; Department of Hepatobiliary and Pancreatic Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou 310014, China; Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou 310000, China.
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10
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Topchieva LV, Kurbatova IV, Dudanova OP, Vasileva AV, Zhulai GA. Immune cell balance as potential biomarker of progressing non-alcoholic fatty liver disease. GENES & CELLS 2024; 19:105-125. [DOI: 10.17816/gc610252] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a widespread chronic, slowly progressive metabolic multifactorial disease. It is represented by several clinical and morphological forms: steatosis, nonalcoholic steatohepatitis (NASH) (with or without fibrosis), and liver cirrhosis. The search for minimally invasive and cost-effective biomarkers of NAFLD is a key task in the diagnosis, staging of progression, and long-term monitoring of NAFLD. This article discusses the possibility of using immune cell balance as potential minimally invasive peripheral markers of NAFLD progression. In the progression of NASH from steatosis to fibrosis and cirrhosis, inflammation plays an important role because of the activation of Kupffer cells and increased migration of monocytes, dendritic cells, neutrophils, and activated T lymphocytes into the tissues. Macrophages originating from monocytes, with NASH progression, gradually begin to prevail over the pool of resident macrophages. The risk of NASH and fibrosis development in patients with NAFLD increases with the ratio of neutrophils/lymphocytes in the liver. An increase in the Th17 cell count and a decrease in T-regulatory cell count can contribute to increased hepatic steatosis and inflammation development in NAFLD and accelerate the transition from simple steatosis to steatohepatitis and fibrosis. Information on the participation of noncoding RNAs in the regulation of the balance of immune cells in NAFLD is presented, which also allows us to consider them as additional, along with cellular, markers of disease progression.
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11
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Zhao W, Li M, Song S, Zhi Y, Huan C, Lv G. The role of natural killer T cells in liver transplantation. Front Cell Dev Biol 2024; 11:1274361. [PMID: 38250325 PMCID: PMC10796773 DOI: 10.3389/fcell.2023.1274361] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Accepted: 12/15/2023] [Indexed: 01/23/2024] Open
Abstract
Natural killer T cells (NKTs) are innate-like lymphocytes that are abundant in the liver and participate in liver immunity. NKT cells express both NK cell and T cell markers, modulate innate and adaptive immune responses. Type I and Type II NKT cells are classified according to the TCR usage, while they recognize lipid antigen in a non-classical major histocompatibility (MHC) molecule CD1d-restricted manner. Once activated, NKT cells can quickly produce cytokines and chemokines to negatively or positively regulate the immune responses, depending on the different NKT subsets. In liver transplantation (LTx), the immune reactions in a series of processes determine the recipients' long-term survival, including ischemia-reperfusion injury, alloresponse, and post-transplant infection. This review provides insight into the research on NKT cells subpopulations in LTx immunity during different processes, and discusses the shortcomings of the current research on NKT cells. Additionally, the CD56-expressing T cells are recognized as a NK-like T cell population, they were also discussed during these processes.
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Affiliation(s)
- Wenchao Zhao
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Mingqian Li
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Shifei Song
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Yao Zhi
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Chen Huan
- Center of Infectious Diseases and Pathogen Biology, Institute of Virology and AIDS Research, Key Laboratory of Organ Regeneration and Transplantation of The Ministry of Education, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Guoyue Lv
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, Jilin, China
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12
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Zhang Q, Li Y, Sui P, Sun XH, Gao Y, Wang CY. MALDI mass spectrometry imaging discloses the decline of sulfoglycosphingolipid and glycerophosphoinositol species in the brain regions related to cognition in a mouse model of Alzheimer's disease. Talanta 2024; 266:125022. [PMID: 37619472 DOI: 10.1016/j.talanta.2023.125022] [Citation(s) in RCA: 11] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Revised: 07/11/2023] [Accepted: 07/31/2023] [Indexed: 08/26/2023]
Abstract
Aging and neurodegenerative disease are accompanied by lipid perturbations in the brain. Understanding the changes in the contents and functional activity of lipids remains a challenge not only because of the many areas in which lipids perform bioactivities but also because of the technical limitations in identifying lipids and their metabolites. In the present study, we aimed to evaluate how brain lipids are altered in Alzheimer's disease (AD)-like pathology by using mass spectrometry imaging (MSI). The spatial distributions and relative abundances of lipids in the brains were compared between APP/PS1 mice and their age-matched wild-type (WT) mice by matrix-assisted laser desorption ionization (MALDI) MSI assays. The comparisons were correlated with the analysis using a spectrophotometric method to determine the relative contents of sulfatides in different brain regions. Significant changes of brain lipids between APP/PS1 and WT mice were identified: eight sulfoglycosphingolipid species, namely, sulfatides/sulfated hexosyl ceramides (ShexCer) and two glycerophosphoinositol (GroPIn) species, PI 36:4 and PI 38:4. The declines in the spatial distributions of these ShexCer and GroPIn species in the APP/PS1 mice brains were associated with learning- and memory-related brain regions. Compared with young WT mice, aged WT mice showed significant decreases in the levels of these ShexCer and GroPIn species. Our results provide technical clues for assessing the impact of brain lipid metabolism on the senescent and neurodegenerative brain. The decline in sulfatides and GroPIns may be crucial markers during brain senescence and AD pathology. Appropriate lipid complementation might be important potentials as a therapeutic strategy for AD.
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Affiliation(s)
- Qi Zhang
- Key Laboratory of Major Chronic Diseases of Nervous System of Liaoning Province, Health Sciences Institute of China Medical University, Shenyang, 110122, China; Key Laboratory of Medical Cell Biology of Ministry of Education, Health Sciences Institute of China Medical University, Shenyang, 110122, China
| | - Yan Li
- Key Laboratory of Major Chronic Diseases of Nervous System of Liaoning Province, Health Sciences Institute of China Medical University, Shenyang, 110122, China; Key Laboratory of Medical Cell Biology of Ministry of Education, Health Sciences Institute of China Medical University, Shenyang, 110122, China
| | - Ping Sui
- Key Laboratory of Major Chronic Diseases of Nervous System of Liaoning Province, Health Sciences Institute of China Medical University, Shenyang, 110122, China; Key Laboratory of Medical Cell Biology of Ministry of Education, Health Sciences Institute of China Medical University, Shenyang, 110122, China
| | - Xue-Heng Sun
- Key Laboratory of Major Chronic Diseases of Nervous System of Liaoning Province, Health Sciences Institute of China Medical University, Shenyang, 110122, China; Key Laboratory of Medical Cell Biology of Ministry of Education, Health Sciences Institute of China Medical University, Shenyang, 110122, China
| | - Yufei Gao
- Key Laboratory of Major Chronic Diseases of Nervous System of Liaoning Province, Health Sciences Institute of China Medical University, Shenyang, 110122, China; Key Laboratory of Medical Cell Biology of Ministry of Education, Health Sciences Institute of China Medical University, Shenyang, 110122, China
| | - Chun-Yan Wang
- Key Laboratory of Major Chronic Diseases of Nervous System of Liaoning Province, Health Sciences Institute of China Medical University, Shenyang, 110122, China; Key Laboratory of Medical Cell Biology of Ministry of Education, Health Sciences Institute of China Medical University, Shenyang, 110122, China; Translational Medicine Laboratory, Basic College of Medicine, Jilin Medical University, No.5 Jilin Street, Gaoxin Area, Jilin, 132013, China.
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13
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Heo MJ, Suh JH, Poulsen KL, Ju C, Kim KH. Updates on the Immune Cell Basis of Hepatic Ischemia-Reperfusion Injury. Mol Cells 2023; 46:527-534. [PMID: 37691258 PMCID: PMC10495686 DOI: 10.14348/molcells.2023.0099] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Revised: 06/19/2023] [Accepted: 07/21/2023] [Indexed: 09/12/2023] Open
Abstract
Liver ischemia-reperfusion injury (IRI) is the main cause of organ dysfunction and failure after liver surgeries including organ transplantation. The mechanism of liver IRI is complex and numerous signals are involved but cellular metabolic disturbances, oxidative stress, and inflammation are considered the major contributors to liver IRI. In addition, the activation of inflammatory signals exacerbates liver IRI by recruiting macrophages, dendritic cells, and neutrophils, and activating NK cells, NKT cells, and cytotoxic T cells. Technological advances enable us to understand the role of specific immune cells during liver IRI. Accordingly, therapeutic strategies to prevent or treat liver IRI have been proposed but no definitive and effective therapies exist yet. This review summarizes the current update on the immune cell functions and discusses therapeutic potentials in liver IRI. A better understanding of this complex and highly dynamic process may allow for the development of innovative therapeutic approaches and optimize patient outcomes.
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Affiliation(s)
- Mi Jeong Heo
- Department of Anesthesiology, Critical Care and Pain Medicine and Center for Perioperative Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Ji Ho Suh
- Department of Anesthesiology, Critical Care and Pain Medicine and Center for Perioperative Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Kyle L. Poulsen
- Department of Anesthesiology, Critical Care and Pain Medicine and Center for Perioperative Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Cynthia Ju
- Department of Anesthesiology, Critical Care and Pain Medicine and Center for Perioperative Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Kang Ho Kim
- Department of Anesthesiology, Critical Care and Pain Medicine and Center for Perioperative Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
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14
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Kumar V, Hertz M, Agro A, Byrne AJ. Type 1 invariant natural killer T cells in chronic inflammation and tissue fibrosis. Front Immunol 2023; 14:1260503. [PMID: 37818376 PMCID: PMC10561218 DOI: 10.3389/fimmu.2023.1260503] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Accepted: 09/06/2023] [Indexed: 10/12/2023] Open
Abstract
Chronic tissue inflammation often results in fibrosis characterized by the accumulation of extracellular matrix components remodeling normal tissue architecture and function. Recent studies have suggested common immune mechanisms despite the complexity of the interactions between tissue-specific fibroblasts, macrophages, and distinct immune cell populations that mediate fibrosis in various tissues. Natural killer T (NKT) cells recognizing lipid antigens bound to CD1d molecules have been shown to play an important role in chronic inflammation and fibrosis. Here we review recent data in both experimental models and in humans that suggest a key role of type 1 invariant NKT (iNKT) cell activation in the progression of inflammatory cascades leading to recruitment of neutrophils and activation of the inflammasome, macrophages, fibroblasts, and, ultimately, fibrosis. Emerging evidence suggests that iNKT-associated mechanisms contribute to type 1, type 2 and type 3 immune pathways mediating tissue fibrosis, including idiopathic pulmonary fibrosis (IPF). Thus, targeting a pathway upstream of these immune mechanisms, such as the inhibition of iNKT activation, may be important in modulating various fibrotic conditions.
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Affiliation(s)
- Vipin Kumar
- Laboratory of Immune Regulation, Department of Medicine, University of California San Diego, La Jolla, CA, United States
- GRI Bio, La Jolla, CA, United States
| | | | | | - Adam J. Byrne
- National Heart and Lung Institute, Imperial College London, London, United Kingdom
- School of Medicine and Conway Institute for Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland
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15
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Yang X, Li Q, Liu W, Zong C, Wei L, Shi Y, Han Z. Mesenchymal stromal cells in hepatic fibrosis/cirrhosis: from pathogenesis to treatment. Cell Mol Immunol 2023; 20:583-599. [PMID: 36823236 PMCID: PMC10229624 DOI: 10.1038/s41423-023-00983-5] [Citation(s) in RCA: 49] [Impact Index Per Article: 24.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Accepted: 01/29/2023] [Indexed: 02/25/2023] Open
Abstract
Hepatic fibrosis/cirrhosis is a significant health burden worldwide, resulting in liver failure or hepatocellular carcinoma (HCC) and accounting for many deaths each year. The pathogenesis of hepatic fibrosis/cirrhosis is very complex, which makes treatment challenging. Endogenous mesenchymal stromal cells (MSCs) have been shown to play pivotal roles in the pathogenesis of hepatic fibrosis. Paradoxically, exogenous MSCs have also been used in clinical trials for liver cirrhosis, and their effectiveness has been observed in most completed clinical trials. There are still many issues to be resolved to promote the use of MSCs in the clinic in the future. In this review, we will examine the controversial role of MSCs in the pathogenesis and treatment of hepatic fibrosis/cirrhosis. We also investigated the clinical trials involving MSCs in liver cirrhosis, summarized the parameters that need to be standardized, and discussed how to promote the use of MSCs from a clinical perspective.
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Affiliation(s)
- Xue Yang
- Department of Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Naval Medical University, Shanghai, 200438, China
- Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer, Ministry of Education, Eastern Hepatobiliary Surgery Hospital/National Center for Liver Cancer, Naval Medical University, Shanghai, 200438, China
- The Third Affiliated Hospital of Soochow University, Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, Key Laboratory of Stem Cells and Medical Biomaterials of Jiangsu Province, Medical College of Soochow University, Soochow University, Suzhou, 215000, China
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, 00133, Rome, Italy
| | - Qing Li
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Wenting Liu
- Department of Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Naval Medical University, Shanghai, 200438, China
- Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer, Ministry of Education, Eastern Hepatobiliary Surgery Hospital/National Center for Liver Cancer, Naval Medical University, Shanghai, 200438, China
| | - Chen Zong
- Department of Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Naval Medical University, Shanghai, 200438, China
- Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer, Ministry of Education, Eastern Hepatobiliary Surgery Hospital/National Center for Liver Cancer, Naval Medical University, Shanghai, 200438, China
| | - Lixin Wei
- Department of Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Naval Medical University, Shanghai, 200438, China
- Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer, Ministry of Education, Eastern Hepatobiliary Surgery Hospital/National Center for Liver Cancer, Naval Medical University, Shanghai, 200438, China
| | - Yufang Shi
- The Third Affiliated Hospital of Soochow University, Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, Key Laboratory of Stem Cells and Medical Biomaterials of Jiangsu Province, Medical College of Soochow University, Soochow University, Suzhou, 215000, China.
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, 00133, Rome, Italy.
| | - Zhipeng Han
- Department of Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Naval Medical University, Shanghai, 200438, China.
- Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer, Ministry of Education, Eastern Hepatobiliary Surgery Hospital/National Center for Liver Cancer, Naval Medical University, Shanghai, 200438, China.
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16
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Huang XF, Fu LS, Cai QQ, Fan F. Prognostic and immunological role of sulfatide-related lncRNAs in hepatocellular carcinoma. Front Oncol 2023; 13:1091132. [PMID: 36816914 PMCID: PMC9929346 DOI: 10.3389/fonc.2023.1091132] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2022] [Accepted: 01/18/2023] [Indexed: 02/04/2023] Open
Abstract
Background Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver. Long non-coding RNAs (lncRNAs) play important roles in the occurrence and development of HCC through multiple pathways. Our previous study reported the specific molecular mechanism for sulfatide regulation of integrin αV expression and cell adhesion in HCC cells through lncRNA AY927503. Next, it is necessary to identify more sulfatide-related lncRNAs, explore their clinical signifcance, and determine new targeted treatment strategies. Methods Microarrays were used to screen a complete set of lncRNAs with different expression profiles in sulfatide-treated cells. Sulfatide-related lncRNAs expression data and corresponding HCC patient survival information were obtained from the The Cancer Genome Atlas (TCGA) database, and the prognosis prediction model was constructed based on Cox regression analysis. Methylated RNA immunoprecipitation with next generation sequencing (MeRIP-seq) was used to detemine the effect of sulfatide on lncRNAs m6A modification. Tumor Immune Estimation Resource (TIMER) and Gene set nnrichment analysis (GSEA) were utilized to enrich the immune and functional pathways of sulfatide-related lncRNAs. Results A total of 85 differentially expressed lncRNAs (|Fold Change (FC)|>2, P<0.05) were screened in sulfatide-treated HCC cells. As a result, 24 sulfatide-related lncRNAs were highly expressed in HCC tissues, six of which were associated with poor prognosis in HCC patients. Based on thses data, a sulfatide-related lncRNAs prognosis assessment model for HCC was constructed. According to this risk score analysis, the overall survival (OS) curve showed that the OS of high-risk patients was significantly lower than that of low-risk patients (P<0.05). Notably, the expression difference in sulfatide-related lncRNA NRSN2-AS1 may be related to sulfatide-induced RNA m6A methylation. In addition, the expression level of NRSN2-AS1 was significantly positively correlated with immune cell infiltration in HCC and participated in the peroxisome and Peroxisome proliferator-activated receptor (PPAR) signaling pathways. Conclusions In conclusion, sulfatide-related lncRNAs might be promising prognostic and therapeutic targets for HCC.
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Affiliation(s)
- Xing Feng Huang
- Department of Biliary Tract Surgery, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Li Sheng Fu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Key Lab of Glycoconjugate Research, Ministry of Public Health, Shanghai, China
| | - Qian Qian Cai
- Shanghai Key Laboratory of Molecular Imaging, Shanghai University of Medicine and Health Sciences, Shanghai, China
| | - Fei Fan
- Department of The Second Ward of Special Treatment, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, China
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17
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The Tumor Microenvironment of Hepatocellular Carcinoma: Untying an Intricate Immunological Network. Cancers (Basel) 2022; 14:cancers14246151. [PMID: 36551635 PMCID: PMC9776867 DOI: 10.3390/cancers14246151] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 12/06/2022] [Accepted: 12/11/2022] [Indexed: 12/23/2022] Open
Abstract
HCC, the most prevalent form of primary liver cancer, is prototypically an inflammation-driven cancer developing after years of inflammatory insults. Consequently, the hepatic microenvironment is a site of complex immunological activities. Moreover, the tolerogenic nature of the liver can act as a barrier to anti-tumor immunity, fostering cancer progression and resistance to immunotherapies based on immune checkpoint inhibitors (ICB). In addition to being a site of primary carcinogenesis, many cancer types have high tropism for the liver, and patients diagnosed with liver metastasis have a dismal prognosis. Therefore, understanding the immunological networks characterizing the tumor microenvironment (TME) of HCC will deepen our understanding of liver immunity, and it will underpin the dominant mechanisms controlling both spontaneous and therapy-induced anti-tumor immune responses. Herein, we discuss the contributions of the cellular and molecular components of the liver immune contexture during HCC onset and progression by underscoring how the balance between antagonistic immune responses can recast the properties of the TME and the response to ICB.
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18
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Roushansarai NS, Pascher A, Becker F. Innate Immune Cells during Machine Perfusion of Liver Grafts-The Janus Face of Hepatic Macrophages. J Clin Med 2022; 11:jcm11226669. [PMID: 36431146 PMCID: PMC9696117 DOI: 10.3390/jcm11226669] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2022] [Revised: 11/08/2022] [Accepted: 11/09/2022] [Indexed: 11/13/2022] Open
Abstract
Machine perfusion is an emerging technology in the field of liver transplantation. While machine perfusion has now been implemented in clinical routine throughout transplant centers around the world, a debate has arisen regarding its concurrent effect on the complex hepatic immune system during perfusion. Currently, our understanding of the perfusion-elicited processes involving innate immune cells remains incomplete. Hepatic macrophages (Kupffer cells) represent a special subset of hepatic immune cells with a dual pro-inflammatory, as well as a pro-resolving and anti-inflammatory, role in the sequence of ischemia-reperfusion injury. The purpose of this review is to provide an overview of the current data regarding the immunomodulatory role of machine perfusion and to emphasize the importance of macrophages for hepatic ischemia-reperfusion injury.
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19
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Immune response associated with ischemia and reperfusion injury during organ transplantation. Inflamm Res 2022; 71:1463-1476. [PMID: 36282292 PMCID: PMC9653341 DOI: 10.1007/s00011-022-01651-6] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Revised: 09/20/2022] [Accepted: 09/21/2022] [Indexed: 12/03/2022] Open
Abstract
Background Ischemia and reperfusion injury (IRI) is an ineluctable immune-related pathophysiological process during organ transplantation, which not only causes a shortage of donor organs, but also has long-term and short-term negative consequences on patients. Severe IRI-induced cell death leads to the release of endogenous substances, which bind specifically to receptors on immune cells to initiate an immune response. Although innate and adaptive immunity have been discovered to play essential roles in IRI in the context of organ transplantation, the pathway and precise involvement of the immune response at various stages has not yet to be elucidated. Methods We combined “IRI” and “organ transplantation” with keywords, respectively such as immune cells, danger signal molecules, macrophages, neutrophils, natural killer cells, complement cascade, T cells or B cells in PubMed and the Web of Science to search for relevant literatures. Conclusion Comprehension of the immune mechanisms involved in organ transplantation is promising for the treatment of IRI, this review summarizes the similarities and differences in both innate and adaptive immunity and advancements in the immune response associated with IRI during diverse organ transplantation.
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20
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Sirajuddin N, Yin XT, Stuart PM. Role of NK T cells in transplantation with particular emphasis on corneal transplantation. Transpl Immunol 2022; 75:101727. [PMID: 36183944 DOI: 10.1016/j.trim.2022.101727] [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: 06/08/2022] [Revised: 09/15/2022] [Accepted: 09/25/2022] [Indexed: 11/18/2022]
Abstract
Natural killer T cells (NKT cells) are a unique subset of the immune system that possess characteristics of both an innate and adaptive immune response. This study reviews the reported roles of NKT cells in different solid transplantations such as cardiac, skin, liver, and corneal grafts as well as investigates a novel role of NKT cells in steroid-resistant corneal rejections. It is unknown why there is late corneal graft rejection despite being treated with immunosuppression. Our experimental data suggests NKT cells are playing a crucial part in steroid-resistant late graft rejections. While the pathophysiology of acute rejection is better understood, the process of chronic graft rejection is much less clear. Our data suggests NKT cells as a potential therapeutic target to prevent chronic transplant rejection which needs further investigation.
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Affiliation(s)
- Nadia Sirajuddin
- Department of Ophthalmology, Saint Louis University School of Medicine, St. Louis, MO, USA
| | - Xiao-Tang Yin
- Department of Ophthalmology, Saint Louis University School of Medicine, St. Louis, MO, USA
| | - Patrick M Stuart
- Department of Ophthalmology, Saint Louis University School of Medicine, St. Louis, MO, USA.
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21
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Liu H, Wang J, Ding Y, Shi X, Ren H. Antibiotic pretreatment attenuates liver ischemia-reperfusion injury by Farnesoid X receptor activation. Cell Death Dis 2022; 13:484. [PMID: 35597796 PMCID: PMC9124217 DOI: 10.1038/s41419-022-04955-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Revised: 05/10/2022] [Accepted: 05/13/2022] [Indexed: 12/14/2022]
Abstract
Prophylactic antibiotics (Abx) are used before liver surgery, and the influence of antibiotic pretreatment on hepatic ischemia-reperfusion injury (IRI) remains unclear. Hence, we explored the impact of Abx pretreatment on hepatic IRI in the present work. The gut microbiota has an essential role in hepatic bile acid (BA) metabolism, and we assumed that depletion of the gut microbiota could affect the composition of hepatic BAs and affect liver IRI. The IRI model demonstrated that Abx pretreatment attenuated liver IRI by alleviating cell apoptosis, reducing the inflammatory response, and decreasing the recruitment of CCR2+ monocytes. Mechanistically, Abx pretreatment reshaped the gut microbiota, especially decreasing the relative abundance of Firmicutes and increasing the relative abundance of Clostridium, which were related to the transformation of BAs and were consistent with the altered bile acid species (unconjugated BAs, especially UDCA). These altered BAs are known FXR agonists and lead to the activation of the farnesoid X receptor (FXR), which can directly bind to the FXR response element (FXRE) harbored in the TLR4 promoter and further suppress downstream mitogen-activated protein kinase (MAPK) and nuclear kappa B (NF-κB) pathways. Meanwhile, the CCL2-CCR2 axis was also involved in the process of FXR activation, as we confirmed both in vivo and in vitro. Importantly, we proved the importance of FXR in mice and clinical occlusion samples, which were inversely correlated with liver injury. Taken together, our study identified that Abx pretreatment before liver resection was a beneficial event by activating FXR, which might become a potential therapeutic target in treating liver injury.
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Affiliation(s)
- Hanyi Liu
- Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Jinglin Wang
- Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
- Institute of Hepatobiliary Surgery, Nanjing University, Nanjing, China
| | - Yitao Ding
- Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China.
- Institute of Hepatobiliary Surgery, Nanjing University, Nanjing, China.
| | - Xiaolei Shi
- Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China.
- Institute of Hepatobiliary Surgery, Nanjing University, Nanjing, China.
| | - Haozhen Ren
- Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China.
- Institute of Hepatobiliary Surgery, Nanjing University, Nanjing, China.
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22
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Liggett JR, Kang J, Ranjit S, Rodriguez O, Loh K, Patil D, Cui Y, Duttargi A, Nguyen S, He B, Lee Y, Oza K, Frank BS, Kwon D, Li HH, Kallakury B, Libby A, Levi M, Robson SC, Fishbein TM, Cui W, Albanese C, Khan K, Kroemer A. Oral N-acetylcysteine decreases IFN-γ production and ameliorates ischemia-reperfusion injury in steatotic livers. Front Immunol 2022; 13:898799. [PMID: 36148239 PMCID: PMC9486542 DOI: 10.3389/fimmu.2022.898799] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Accepted: 07/11/2022] [Indexed: 12/05/2022] Open
Abstract
Type 1 Natural Killer T-cells (NKT1 cells) play a critical role in mediating hepatic ischemia-reperfusion injury (IRI). Although hepatic steatosis is a major risk factor for preservation type injury, how NKT cells impact this is understudied. Given NKT1 cell activation by phospholipid ligands recognized presented by CD1d, we hypothesized that NKT1 cells are key modulators of hepatic IRI because of the increased frequency of activating ligands in the setting of hepatic steatosis. We first demonstrate that IRI is exacerbated by a high-fat diet (HFD) in experimental murine models of warm partial ischemia. This is evident in the evaluation of ALT levels and Phasor-Fluorescence Lifetime (Phasor-FLIM) Imaging for glycolytic stress. Polychromatic flow cytometry identified pronounced increases in CD45+CD3+NK1.1+NKT1 cells in HFD fed mice when compared to mice fed a normal diet (ND). This observation is further extended to IRI, measuring ex vivo cytokine expression in the HFD and ND. Much higher interferon-gamma (IFN-γ) expression is noted in the HFD mice after IRI. We further tested our hypothesis by performing a lipidomic analysis of hepatic tissue and compared this to Phasor-FLIM imaging using "long lifetime species", a byproduct of lipid oxidation. There are higher levels of triacylglycerols and phospholipids in HFD mice. Since N-acetylcysteine (NAC) is able to limit hepatic steatosis, we tested how oral NAC supplementation in HFD mice impacted IRI. Interestingly, oral NAC supplementation in HFD mice results in improved hepatic enhancement using contrast-enhanced magnetic resonance imaging (MRI) compared to HFD control mice and normalization of glycolysis demonstrated by Phasor-FLIM imaging. This correlated with improved biochemical serum levels and a decrease in IFN-γ expression at a tissue level and from CD45+CD3+CD1d+ cells. Lipidomic evaluation of tissue in the HFD+NAC mice demonstrated a drastic decrease in triacylglycerol, suggesting downregulation of the PPAR-γ pathway.
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Affiliation(s)
- Jedson R Liggett
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, DC, United States.,Department of Surgery, Naval Medical Center Portsmouth, Portsmouth, VA, United States
| | - Jiman Kang
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, DC, United States.,Department of Biochemistry and Molecular & Cellular Biology, Georgetown University, Washington, DC, United States
| | - Suman Ranjit
- Department of Biochemistry and Molecular & Cellular Biology, Georgetown University, Washington, DC, United States.,Microscopy & Imaging Shared Resource, Georgetown University, Washington, DC, United States
| | - Olga Rodriguez
- Center for Translational Imaging, Georgetown University Medical Center, Washington, DC, United States.,Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, United States
| | - Katrina Loh
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, DC, United States
| | - Digvijay Patil
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, DC, United States
| | - Yuki Cui
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, DC, United States
| | - Anju Duttargi
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, United States
| | - Sang Nguyen
- Center for Translational Imaging, Georgetown University Medical Center, Washington, DC, United States
| | - Britney He
- Center for Translational Imaging, Georgetown University Medical Center, Washington, DC, United States
| | - Yichien Lee
- Center for Translational Imaging, Georgetown University Medical Center, Washington, DC, United States.,Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, United States
| | - Kesha Oza
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, DC, United States
| | - Brett S Frank
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, DC, United States
| | - DongHyang Kwon
- Department of Pathology, MedStar Georgetown University Hospital, Washington, DC, United States
| | - Heng-Hong Li
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, United States
| | - Bhaskar Kallakury
- Department of Pathology, MedStar Georgetown University Hospital, Washington, DC, United States
| | - Andrew Libby
- Division of Endocrinology, Metabolism, & Diabetes, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Moshe Levi
- Department of Biochemistry and Molecular & Cellular Biology, Georgetown University, Washington, DC, United States
| | - Simon C Robson
- Departments of Anesthesiology and Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
| | - Thomas M Fishbein
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, DC, United States
| | - Wanxing Cui
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, DC, United States.,Department of Biochemistry and Molecular & Cellular Biology, Georgetown University, Washington, DC, United States
| | - Chris Albanese
- Center for Translational Imaging, Georgetown University Medical Center, Washington, DC, United States.,Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, United States.,Department of Radiology, MedStar Georgetown University Hospital, Washington, DC, United States
| | - Khalid Khan
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, DC, United States
| | - Alexander Kroemer
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, DC, United States
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23
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Goto T, Ito Y, Satoh M, Nakamoto S, Nishizawa N, Hosono K, Naitoh T, Eshima K, Iwabuchi K, Hiki N, Amano H. Activation of iNKT Cells Facilitates Liver Repair After Hepatic Ischemia Reperfusion Injury Through Acceleration of Macrophage Polarization. Front Immunol 2021; 12:754106. [PMID: 34691073 PMCID: PMC8526965 DOI: 10.3389/fimmu.2021.754106] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Accepted: 09/20/2021] [Indexed: 12/15/2022] Open
Abstract
Macrophage polarization is critical for liver tissue repair following acute liver injury. However, the underlying mechanisms of macrophage phenotype switching are not well defined. Invariant natural killer T (iNKT) cells orchestrate tissue inflammation and tissue repair by regulating cytokine production. Herein, we examined whether iNKT cells played an important role in liver repair after hepatic ischemia-reperfusion (I/R) injury by affecting macrophage polarization. To this end, we subjected male C57BL/6 mice to hepatic I/R injury, and mice received an intraperitoneal (ip) injection of α-galactosylceramide (α-GalCer) or vehicle. Compared with that of the vehicle, α-GalCer administration resulted in the promotion of liver repair accompanied by acceleration of macrophage differentiation and by increases in the numbers of Ly6Chigh pro-inflammatory macrophages and Ly6Clow reparative macrophages. iNKT cells activated with α-GalCer produced interleukin (IL)-4 and interferon (IFN)-γ. Treatment with anti-IL-4 antibodies delayed liver repair, which was associated with an increased number of Ly6Chigh macrophages and a decreased number of Ly6Clow macrophages. Treatment with anti-IFN-γ antibodies promoted liver repair, associated with reduced the number of Ly6Chigh macrophages, but did not change the number of Ly6Clow macrophages. Bone marrow-derived macrophages up-regulated the expression of genes related to both a pro-inflammatory and a reparative phenotype when co-cultured with activated iNKT cells. Anti-IL-4 antibodies increased the levels of pro-inflammatory macrophage-related genes and decreased those of reparative macrophage-related genes in cultured macrophages, while anti-IFN-γ antibodies reversed the polarization of macrophages. Cd1d-deficient mice showed delayed liver repair and suppressed macrophage switching, compared with that in wild-type mice. These results suggest that the activation of iNKT cells by α-GalCer facilitated liver repair after hepatic I/R injury by both IL-4-and IFN-γ-mediated acceleration of macrophage polarization. Therefore, the activation of iNKT cells may represent a therapeutic tool for liver repair after hepatic I/R injury.
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Affiliation(s)
- Takuya Goto
- Department of Molecular Pharmacology, Graduate School of Medical Sciences, Kitasato University, Sagamihara, Japan.,Department of Pharmacology, Kitasato University School of Medicine, Sagamihara, Japan.,Department of Lower Gastrointestinal Surgery, Kitasato University School of Medicine, Sagamihara, Japan
| | - Yoshiya Ito
- Department of Molecular Pharmacology, Graduate School of Medical Sciences, Kitasato University, Sagamihara, Japan.,Department of Pharmacology, Kitasato University School of Medicine, Sagamihara, Japan
| | - Masashi Satoh
- Department of Immunology, Kitasato University School of Medicine, Sagamihara, Japan
| | - Shuji Nakamoto
- Department of Molecular Pharmacology, Graduate School of Medical Sciences, Kitasato University, Sagamihara, Japan.,Department of General Pediatric Hepatobiliary Pancreatic Surgery, Kitasato University School of Medicine, Sagamihara, Japan
| | - Nobuyuki Nishizawa
- Department of General Pediatric Hepatobiliary Pancreatic Surgery, Kitasato University School of Medicine, Sagamihara, Japan
| | - Kanako Hosono
- Department of Molecular Pharmacology, Graduate School of Medical Sciences, Kitasato University, Sagamihara, Japan.,Department of Pharmacology, Kitasato University School of Medicine, Sagamihara, Japan
| | - Takeshi Naitoh
- Department of Lower Gastrointestinal Surgery, Kitasato University School of Medicine, Sagamihara, Japan
| | - Koji Eshima
- Department of Immunology, Kitasato University School of Medicine, Sagamihara, Japan
| | - Kazuya Iwabuchi
- Department of Immunology, Kitasato University School of Medicine, Sagamihara, Japan
| | - Naoki Hiki
- Department of Upper Gastrointestinal Surgery, Kitasato University School of Medicine, Sagamihara, Japan
| | - Hideki Amano
- Department of Molecular Pharmacology, Graduate School of Medical Sciences, Kitasato University, Sagamihara, Japan.,Department of Pharmacology, Kitasato University School of Medicine, Sagamihara, Japan
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24
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Type II NKT Cell Agonist, Sulfatide, Is an Effective Adjuvant for Oral Heat-Killed Cholera Vaccines. Vaccines (Basel) 2021; 9:vaccines9060619. [PMID: 34201310 PMCID: PMC8230052 DOI: 10.3390/vaccines9060619] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Revised: 05/27/2021] [Accepted: 06/01/2021] [Indexed: 12/27/2022] Open
Abstract
Oral vaccination has the potential to offer a safer and more efficacious approach for protection against enteric pathogens than injection-based approaches, especially in developing countries. One key advantage is the potential to induce intestinal immune responses in addition to systemic immunity. In general, antigen delivery via the oral route triggers weak immune responses or immunological tolerance. The effectiveness of oral vaccination can be improved by co-administering adjuvants. However, a major challenge is the absence of potent and safe oral adjuvants for clinical application. Here, the Type II NKT cell activator sulfatide is shown for the first time to be an effective oral adjuvant for Vibrio cholerae vaccine antigens in a mouse model. Specifically, administration of sulfatide with the oral cholera vaccine Dukoral® resulted in enhancement of intestinal antigen-specific IgA in addition to Th1 and Th17 immune responses. In summary, sulfatide is a promising adjuvant for inclusion in an oral cholera vaccine and our data further support the potential of adjuvants targeting NKT cells in new vaccine strategies.
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25
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Ahmed O, Robinson MW, O'Farrelly C. Inflammatory processes in the liver: divergent roles in homeostasis and pathology. Cell Mol Immunol 2021; 18:1375-1386. [PMID: 33864004 PMCID: PMC8166849 DOI: 10.1038/s41423-021-00639-2] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Accepted: 01/10/2021] [Indexed: 02/07/2023] Open
Abstract
The hepatic immune system is designed to tolerate diverse harmless foreign moieties to maintain homeostasis in the healthy liver. Constant priming and regulation ensure that appropriate immune activation occurs when challenged by pathogens and tissue damage. Failure to accurately discriminate, regulate, or effectively resolve inflammation offsets this balance, jeopardizing overall tissue health resulting from an either overly tolerant or an overactive inflammatory response. Compelling scientific and clinical evidence links dysregulated hepatic immune and inflammatory responses upon sterile injury to several pathological conditions in the liver, particularly nonalcoholic steatohepatitis and ischemia-reperfusion injury. Murine and human studies have described interactions between diverse immune repertoires and nonhematopoietic cell populations in both physiological and pathological activities in the liver, although the molecular mechanisms driving these associations are not clearly understood. Here, we review the dynamic roles of inflammatory mediators in responses to sterile injury in the context of homeostasis and disease, the clinical implications of dysregulated hepatic immune activity and therapeutic developments to regulate liver-specific immunity.
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Affiliation(s)
- Ola Ahmed
- School of Medicine, Trinity College Dublin, Dublin, Ireland
| | - Mark W Robinson
- Department of Biology, Kathleen Lonsdale Institute for Human Health Research, Maynooth University, Maynooth, Ireland
| | - Cliona O'Farrelly
- School of Medicine, Trinity College Dublin, Dublin, Ireland.
- School of Biochemistry & Immunology, Trinity College Dublin, Dublin 2, Ireland.
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26
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Wang Z, Guo H, Xu R, Zhao CN, Xia Y. The effects of cell surface CD47 downregulation on ischaemia-reperfusion injury during pig liver transplantation. Int J Exp Pathol 2021; 102:140-147. [PMID: 33881787 DOI: 10.1111/iep.12391] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Revised: 01/12/2021] [Accepted: 01/12/2021] [Indexed: 12/20/2022] Open
Abstract
This study aimed to investigate the effect of cell surface CD47 downregulation on ischaemia-reperfusion injury (IRI) during pig liver transplantation. Blood samples were collected from healthy miniature Bama pigs randomly and equally divided into CD47 antagonism (group A), without CD47 antagonism (group B) and a sham group (group C). Blood samples were collected from groups A and B at 0, 8 and 48 hours after establishment of the new liver through an indwelling tube in the right internal jugular vein. Blood samples were collected at the same time points after liver dissociation from group C. The expression of interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α) was detected by enzyme-linked immunosorbent assay (ELISA); CD47 expression was detected by Western blot; and liver function indices, including alanine aminotransferase (ALT) and aspartic transaminase (AST), were directly read by an automatic biochemical analyzer. The concentrations of both receptors in group A were significantly lower than groups B and C, at 8 and 48 hours after establishment of blood flow. At 8 and 48 hours in the new liver stage, the values of CD47 levels, ALT and AST in group A were significantly reduced compared to groups B and C (P < 0.05). The levels of CD47 in the three groups were consistent with the trends of the aforementioned observation indicators. The liver functions of the recipients were significantly improved by reducing the release of the inflammatory mediators. This study provides new ideas and intervention approaches for the treatment of IRI in liver transplantation.
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Affiliation(s)
- Zhi Wang
- Department of Anesthesiology, Shanxi Provincial People's Hospital, Taiyuan, China
| | - Hao Guo
- Department of Anesthesiology, Shanxi Provincial People's Hospital, Taiyuan, China
| | - Rui Xu
- Department of Anesthesiology, Shanxi Provincial People's Hospital, Taiyuan, China
| | - Chun-Ni Zhao
- Department of Health Statistics, School of Public Health, Shanxi Medical University, Taiyuan, China
| | - Yun Xia
- Department of Anesthesiology, Ohio State University College of Medicine, Columbus, OH, USA.,Wenzhou Central Hospital, Wenzhou Medical University, Wenzhou, China
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27
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Zou M, Nong C, Yu Z, Cai H, Jiang Z, Xue R, Huang X, Sun L, Zhang L, Wang X. The role of invariant natural killer T cells and associated immunoregulatory factors in triptolide-induced cholestatic liver injury. Food Chem Toxicol 2020; 146:111777. [DOI: 10.1016/j.fct.2020.111777] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Revised: 09/19/2020] [Accepted: 09/23/2020] [Indexed: 12/23/2022]
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28
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Lymphocyte Immunosuppression and Dysfunction Contributing to Persistent Inflammation, Immunosuppression, and Catabolism Syndrome (PICS). Shock 2020; 55:723-741. [PMID: 33021569 DOI: 10.1097/shk.0000000000001675] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
ABSTRACT Persistent Inflammation, Immune Suppression, and Catabolism Syndrome (PICS) is a disease state affecting patients who have a prolonged recovery after the acute phase of a large inflammatory insult. Trauma and sepsis are two pathologies after which such an insult evolves. In this review, we will focus on the key clinical determinants of PICS: Immunosuppression and cellular dysfunction. Currently, relevant immunosuppressive functions have been attributed to both innate and adaptive immune cells. However, there are significant gaps in our knowledge, as for trauma and sepsis the immunosuppressive functions of these cells have mostly been described in acute phase of inflammation so far, and their clinical relevance for the development of prolonged immunosuppression is mostly unknown. It is suggested that the initial immune imbalance determines the development of PCIS. Additionally, it remains unclear what distinguishes the onset of immune dysfunction in trauma and sepsis and how this drives immunosuppression in these cells. In this review, we will discuss how regulatory T cells (Tregs), innate lymphoid cells, natural killer T cells (NKT cells), TCR-a CD4- CD8- double-negative T cells (DN T cells), and B cells can contribute to the development of post-traumatic and septic immunosuppression. Altogether, we seek to fill a gap in the understanding of the contribution of lymphocyte immunosuppression and dysfunction to the development of chronic immune disbalance. Further, we will provide an overview of promising diagnostic and therapeutic interventions, whose potential to overcome the detrimental immunosuppression after trauma and sepsis is currently being tested.
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29
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van Eijk M, Ferraz MJ, Boot RG, Aerts JMFG. Lyso-glycosphingolipids: presence and consequences. Essays Biochem 2020; 64:565-578. [PMID: 32808655 PMCID: PMC7517347 DOI: 10.1042/ebc20190090] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Revised: 07/14/2020] [Accepted: 07/17/2020] [Indexed: 12/12/2022]
Abstract
Lyso-glycosphingolipids are generated in excess in glycosphingolipid storage disorders. In the course of these pathologies glycosylated sphingolipid species accumulate within lysosomes due to flaws in the respective lipid degrading machinery. Deacylation of accumulating glycosphingolipids drives the formation of lyso-glycosphingolipids. In lysosomal storage diseases such as Gaucher Disease, Fabry Disease, Krabbe disease, GM1 -and GM2 gangliosidosis, Niemann Pick type C and Metachromatic leukodystrophy massive intra-lysosomal glycosphingolipid accumulation occurs. The lysosomal enzyme acid ceramidase generates the deacylated lyso-glycosphingolipid species. This review discusses how the various lyso-glycosphingolipids are synthesized, how they may contribute to abnormal immunity in glycosphingolipid storing lysosomal diseases and what therapeutic opportunities exist.
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Affiliation(s)
- Marco van Eijk
- Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2300 RA, Leiden, The Netherlands
| | - Maria J Ferraz
- Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2300 RA, Leiden, The Netherlands
| | - Rolf G Boot
- Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2300 RA, Leiden, The Netherlands
| | - Johannes M F G Aerts
- Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2300 RA, Leiden, The Netherlands
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30
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Hann A, Osei-Bordom DC, Neil DAH, Ronca V, Warner S, Perera MTPR. The Human Immune Response to Cadaveric and Living Donor Liver Allografts. Front Immunol 2020; 11:1227. [PMID: 32655558 PMCID: PMC7323572 DOI: 10.3389/fimmu.2020.01227] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Accepted: 05/15/2020] [Indexed: 12/13/2022] Open
Abstract
The liver is an important contributor to the human immune system and it plays a pivotal role in the creation of both immunoreactive and tolerogenic conditions. Liver transplantation provides the best chance of survival for both children and adults with liver failure or cancer. With current demand exceeding the number of transplantable livers from donors following brain death, improved knowledge, technical advances and the desire to prevent avoidable deaths has led to the transplantation of organs from living, ABO incompatible (ABOi), cardiac death donors and machine based organ preservation with acceptable results. The liver graft is the most well-tolerated, from an immunological perspective, of all solid organ transplants. Evidence suggests successful cessation of immunosuppression is possible in ~20–40% of liver transplant recipients without immune mediated graft injury, a state known as “operational tolerance.” An immunosuppression free future following liver transplantation is an ambitious but perhaps not unachievable goal. The initial immune response following transplantation is a sterile inflammatory process mediated by the innate system and the mechanisms relate to the preservation-reperfusion process. The severity of this injury is influenced by graft factors and can have significant consequences. There are minimal experimental studies that delineate the differences in the adaptive immune response to the various forms of liver allograft. Apart from ABOi transplants, antibody mediated hyperacute rejection is rare following liver transplant. T-cell mediated rejection is common following liver transplantation and its incidence does not differ between living or deceased donor grafts. Transplantation in the first year of life results in a higher rate of operational tolerance, possibly due to a bias toward Th2 cytokines (IL4, IL10) during this period. This review further describes the current understanding of the immunological response toward liver allografts and highlight the areas of this topic yet to be fully understood.
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Affiliation(s)
- Angus Hann
- The Liver Unit, Queen Elizabeth Hospital Birmingham, Birmingham, United Kingdom.,Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
| | | | - Desley A H Neil
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom.,Department of Cellular Pathology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom
| | - Vincenzo Ronca
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
| | - Suz Warner
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom.,The Liver Unit, Birmingham Children's Hospital, Birmingham, United Kingdom
| | - M Thamara P R Perera
- The Liver Unit, Queen Elizabeth Hospital Birmingham, Birmingham, United Kingdom.,The Liver Unit, Birmingham Children's Hospital, Birmingham, United Kingdom
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31
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Collin R, Lombard-Vadnais F, Hillhouse EE, Lebel MÈ, Chabot-Roy G, Melichar HJ, Lesage S. MHC-Independent Thymic Selection of CD4 and CD8 Coreceptor Negative αβ T Cells. THE JOURNAL OF IMMUNOLOGY 2020; 205:133-142. [PMID: 32434937 DOI: 10.4049/jimmunol.2000156] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/10/2020] [Accepted: 04/23/2020] [Indexed: 12/12/2022]
Abstract
It is becoming increasingly clear that unconventional T cell subsets, such as NKT, γδ T, mucosal-associated invariant T, and CD8αα T cells, each play distinct roles in the immune response. Subsets of these cell types can lack both CD4 and CD8 coreceptor expression. Beyond these known subsets, we identify CD4-CD8-TCRαβ+, double-negative (DN) T cells, in mouse secondary lymphoid organs. DN T cells are a unique unconventional thymic-derived T cell subset. In contrast to CD5high DN thymocytes that preferentially yield TCRαβ+ CD8αα intestinal lymphocytes, we find that mature CD5low DN thymocytes are precursors to peripheral DN T cells. Using reporter mouse strains, we show that DN T cells transit through the immature CD4+CD8+ (double-positive) thymocyte stage. Moreover, we provide evidence that DN T cells can differentiate in MHC-deficient mice. Our study demonstrates that MHC-independent thymic selection can yield DN T cells that are distinct from NKT, γδ T, mucosal-associated invariant T, and CD8αα T cells.
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Affiliation(s)
- Roxanne Collin
- Immunology-Oncology Section, Maisonneuve-Rosemont Hospital Research Center, Montreal, Quebec H1T 2M4, Canada.,Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montreal, Quebec H3C 3J7, Canada
| | - Félix Lombard-Vadnais
- Immunology-Oncology Section, Maisonneuve-Rosemont Hospital Research Center, Montreal, Quebec H1T 2M4, Canada.,Department of Microbiology and Immunology, McGill University, Montreal, Quebec H3A 0G4, Canada; and
| | - Erin E Hillhouse
- Immunology-Oncology Section, Maisonneuve-Rosemont Hospital Research Center, Montreal, Quebec H1T 2M4, Canada
| | - Marie-Ève Lebel
- Immunology-Oncology Section, Maisonneuve-Rosemont Hospital Research Center, Montreal, Quebec H1T 2M4, Canada
| | - Geneviève Chabot-Roy
- Immunology-Oncology Section, Maisonneuve-Rosemont Hospital Research Center, Montreal, Quebec H1T 2M4, Canada
| | - Heather J Melichar
- Immunology-Oncology Section, Maisonneuve-Rosemont Hospital Research Center, Montreal, Quebec H1T 2M4, Canada.,Département de Médecine, Université de Montréal, Montreal, Quebec H3T 1J4, Canada
| | - Sylvie Lesage
- Immunology-Oncology Section, Maisonneuve-Rosemont Hospital Research Center, Montreal, Quebec H1T 2M4, Canada; .,Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montreal, Quebec H3C 3J7, Canada
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Marrero I, Maricic I, Morgan TR, Stolz AA, Schnabl B, Liu ZX, Tsukamoto H, Kumar V. Differential Activation of Unconventional T Cells, Including iNKT Cells, in Alcohol-Related Liver Disease. Alcohol Clin Exp Res 2020; 44:1061-1074. [PMID: 32154597 DOI: 10.1111/acer.14323] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2019] [Accepted: 02/25/2020] [Indexed: 12/13/2022]
Abstract
BACKGROUND Liver is enriched in several innate-like unconventional T cells, but their role in alcohol-related liver disease (ALD) is not fully understood. Studies in several acute alcohol feeding models but not in chronic alcoholic steatohepatitis (ASH) model have shown that invariant natural killer T (iNKT) cells play a pathogenic role in ALD. Here, we investigated the activation of iNKT cells in an intragastric (iG) infusion model of chronic ASH as well as the frequency and cytokine phenotype of 3 different unconventional T cells: iNKT, mucosal-associated invariant T (MAIT), and CD8+ CD161hi Vα7.2- cells in peripheral blood of ALD patients. METHODS Hepatic iNKT cells were investigated using the iG model of chronic ASH that combines feeding of high-cholesterol/high-fat diet (HCFD) with intragastric feeding of ethanol diet (HCFD + iG Alc). Human iNKT, MAIT, and CD8+ CD161hi Vα7.2- cells were examined by flow cytometry in peripheral blood of patients with severe alcoholic hepatitis (SAH) and chronic alcoholics (ChA) and compared with healthy controls. RESULTS In the iG model of chronic ASH, IFNγ+ iNKT cells accumulate in their livers compared with pair-fed control mice and activated hepatic iNKT cells show high expression of Fas and FasL. Notably, IFNγ+ iNKT cells are also significantly increased in peripheral blood of ChA patients compared with SAH patients. MAIT cells are significantly reduced in all ALD patients, but CD8+ CD161hi Vα7.2- cells are increased in SAH patients. Although MAIT and CD8+ CD161hi Vα7.2- cells displayed a similar cytokine production profile, the production of IFNγ and TNFα is significantly increased in SAH patients, while significant IL-17A production is found in ChA patients. CONCLUSIONS We found that the 3 unconventional T cells are activated in ALD patients showing interesting differences in their frequency and cytokine production profile between SAH and ChA patients. In the iG murine model of chronic ASH, iNKT cells are also activated secreting proinflammatory cytokines suggesting their involvement in liver disease.
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Affiliation(s)
- Idania Marrero
- From the, Division of Gastroenterology, (IdM, IgM, BS, VK), Department of Medicine, University of California San Diego, La Jolla, California
| | - Igor Maricic
- From the, Division of Gastroenterology, (IdM, IgM, BS, VK), Department of Medicine, University of California San Diego, La Jolla, California
| | - Timothy R Morgan
- Gastroenterology Section, (TRM), VA Long Beach Healthcare System, Long Beach, California
| | - Andrew A Stolz
- Division of Gastrointestinal and Liver Diseases, (AAS), Keck School of Medicine of University of Southern California, Los Angeles, California
| | - Bernd Schnabl
- From the, Division of Gastroenterology, (IdM, IgM, BS, VK), Department of Medicine, University of California San Diego, La Jolla, California.,VA San Diego Healthcare System, (BS), San Diego, California
| | - Zhang-Xu Liu
- Research Center for Liver Diseases, (Z-XL), Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Hidekazu Tsukamoto
- Southern California Research Center for ALPD and Cirrhosis, (HT), Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California.,VA Greater Los Angeles Healthcare System, (HT), Los Angeles, California
| | - Vipin Kumar
- From the, Division of Gastroenterology, (IdM, IgM, BS, VK), Department of Medicine, University of California San Diego, La Jolla, California
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Guo W, Fang H, Cao S, Chen S, Li J, Shi J, Tang H, Zhang Y, Wen P, Zhang J, Wang Z, Shi X, Pang C, Yang H, Hu B, Zhang S. Six-Transmembrane Epithelial Antigen of the Prostate 3 Deficiency in Hepatocytes Protects the Liver Against Ischemia-Reperfusion Injury by Suppressing Transforming Growth Factor-β-Activated Kinase 1. Hepatology 2020; 71:1037-1054. [PMID: 31393024 PMCID: PMC7155030 DOI: 10.1002/hep.30882] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2019] [Accepted: 07/24/2019] [Indexed: 12/17/2022]
Abstract
BACKGROUND AND AIMS Hepatic ischemia-reperfusion (I/R) injury remains a major challenge affecting the morbidity and mortality of liver transplantation. Effective strategies to improve liver function after hepatic I/R injury are limited. Six-transmembrane epithelial antigen of the prostate 3 (Steap3), a key regulator of iron uptake, was reported to be involved in immunity and apoptotic processes in various cell types. However, the role of Steap3 in hepatic I/R-induced liver damage remains largely unclear. APPROACH AND RESULTS In the present study, we found that Steap3 expression was significantly up-regulated in liver tissue from mice subjected to hepatic I/R surgery and primary hepatocytes challenged with hypoxia/reoxygenation insult. Subsequently, global Steap3 knockout (Steap3-KO) mice, hepatocyte-specific Steap3 transgenic (Steap3-HTG) mice, and their corresponding controls were subjected to partial hepatic warm I/R injury. Hepatic histology, the inflammatory response, and apoptosis were monitored to assess liver damage. The molecular mechanisms of Steap3 function were explored in vivo and in vitro. The results demonstrated that, compared with control mice, Steap3-KO mice exhibited alleviated liver damage after hepatic I/R injury, as shown by smaller necrotic areas, lower serum transaminase levels, decreased apoptosis rates, and reduced inflammatory cell infiltration, whereas Steap3-HTG mice had the opposite phenotype. Further molecular experiments showed that Steap3 deficiency could inhibit transforming growth factor-β-activated kinase 1 (TAK1) activation and downstream c-Jun N-terminal kinase (JNK) and p38 signaling during hepatic I/R injury. CONCLUSIONS Steap3 is a mediator of hepatic I/R injury that functions by regulating inflammatory responses as well as apoptosis through TAK1-dependent activation of the JNK/p38 pathways. Targeting hepatocytes, Steap3 may be a promising approach to protect the liver against I/R injury.
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Affiliation(s)
- Wen‐Zhi Guo
- Department of Hepatobiliary and Pancreatic SurgeryThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenan ProvinceChina,Henan Key Laboratory of Digestive Organ TransplantationZhengzhouHenan ProvinceChina,Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan UniversitiesZhengzhouHenan ProvinceChina
| | - Hong‐Bo Fang
- Department of Hepatobiliary and Pancreatic SurgeryThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenan ProvinceChina,Henan Key Laboratory of Digestive Organ TransplantationZhengzhouHenan ProvinceChina,Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan UniversitiesZhengzhouHenan ProvinceChina
| | - Sheng‐Li Cao
- Department of Hepatobiliary and Pancreatic SurgeryThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenan ProvinceChina,Henan Key Laboratory of Digestive Organ TransplantationZhengzhouHenan ProvinceChina,Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan UniversitiesZhengzhouHenan ProvinceChina
| | - San‐Yang Chen
- Department of Hepatobiliary and Pancreatic SurgeryThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenan ProvinceChina,Henan Key Laboratory of Digestive Organ TransplantationZhengzhouHenan ProvinceChina,Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan UniversitiesZhengzhouHenan ProvinceChina
| | - Jie Li
- Department of Hepatobiliary and Pancreatic SurgeryThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenan ProvinceChina,Henan Key Laboratory of Digestive Organ TransplantationZhengzhouHenan ProvinceChina,Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan UniversitiesZhengzhouHenan ProvinceChina
| | - Ji‐Hua Shi
- Department of Hepatobiliary and Pancreatic SurgeryThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenan ProvinceChina,Henan Key Laboratory of Digestive Organ TransplantationZhengzhouHenan ProvinceChina,Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan UniversitiesZhengzhouHenan ProvinceChina
| | - Hong‐Wei Tang
- Henan Key Laboratory of Digestive Organ TransplantationZhengzhouHenan ProvinceChina,Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan UniversitiesZhengzhouHenan ProvinceChina
| | - Yi Zhang
- Department of SurgeryThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenan ProvinceChina
| | - Pei‐Hao Wen
- Department of Hepatobiliary and Pancreatic SurgeryThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenan ProvinceChina,Henan Key Laboratory of Digestive Organ TransplantationZhengzhouHenan ProvinceChina,Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan UniversitiesZhengzhouHenan ProvinceChina
| | - Jia‐Kai Zhang
- Department of Hepatobiliary and Pancreatic SurgeryThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenan ProvinceChina,Henan Key Laboratory of Digestive Organ TransplantationZhengzhouHenan ProvinceChina,Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan UniversitiesZhengzhouHenan ProvinceChina
| | - Zhi‐Hui Wang
- Department of Hepatobiliary and Pancreatic SurgeryThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenan ProvinceChina,Henan Key Laboratory of Digestive Organ TransplantationZhengzhouHenan ProvinceChina,Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan UniversitiesZhengzhouHenan ProvinceChina
| | - Xiao‐Yi Shi
- Department of Hepatobiliary and Pancreatic SurgeryThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenan ProvinceChina,Henan Key Laboratory of Digestive Organ TransplantationZhengzhouHenan ProvinceChina,Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan UniversitiesZhengzhouHenan ProvinceChina
| | - Chun Pang
- Department of Hepatobiliary and Pancreatic SurgeryThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenan ProvinceChina,Henan Key Laboratory of Digestive Organ TransplantationZhengzhouHenan ProvinceChina,Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan UniversitiesZhengzhouHenan ProvinceChina
| | - Han Yang
- Department of Hepatobiliary and Pancreatic SurgeryThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenan ProvinceChina,Henan Key Laboratory of Digestive Organ TransplantationZhengzhouHenan ProvinceChina,Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan UniversitiesZhengzhouHenan ProvinceChina
| | - Bo‐Wen Hu
- Department of Hepatobiliary and Pancreatic SurgeryThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenan ProvinceChina,Henan Key Laboratory of Digestive Organ TransplantationZhengzhouHenan ProvinceChina,Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan UniversitiesZhengzhouHenan ProvinceChina
| | - Shui‐Jun Zhang
- Department of Hepatobiliary and Pancreatic SurgeryThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenan ProvinceChina,Henan Key Laboratory of Digestive Organ TransplantationZhengzhouHenan ProvinceChina,Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan UniversitiesZhengzhouHenan ProvinceChina
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Barbier L, Ferhat M, Salamé E, Robin A, Herbelin A, Gombert JM, Silvain C, Barbarin A. Interleukin-1 Family Cytokines: Keystones in Liver Inflammatory Diseases. Front Immunol 2019; 10:2014. [PMID: 31507607 PMCID: PMC6718562 DOI: 10.3389/fimmu.2019.02014] [Citation(s) in RCA: 102] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2019] [Accepted: 08/08/2019] [Indexed: 12/12/2022] Open
Abstract
The pyrogenic property being the first activity described, members of the interleukin-1 superfamily (IL-1α, IL-1β, IL-18, and the newest members: IL-33, IL-36, IL-37, and IL-38) are now known to be involved in several inflammatory diseases such as obesity, atherosclerosis, cancer, viral and parasite infections, and auto-inflammatory syndromes as well as liver diseases. Inflammation processes are keystones of chronic liver diseases, of which the etiology may be viral or toxic, as in alcoholic or non-alcoholic liver diseases. Inflammation is also at stake in acute liver failure involving massive necrosis, and in ischemia-reperfusion injury in the setting of liver transplantation. The role of the IL-1 superfamily of cytokines and receptors in liver diseases can be either protective or pro-inflammatory, depending on timing and the environment. Our review provides an overview of current understanding of the IL-1 family members in liver inflammation, highlighting recent key investigations, and therapeutic perspectives. We have tried to apply the concept of trained immunity to liver diseases, based on the role of the members of the IL-1 superfamily, first of all IL-1β but also IL-18 and IL-33, in modulating innate lymphoid immunity carried by natural killer cells, innate lymphoid cells or innate T-αβ lymphocytes.
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Affiliation(s)
- Louise Barbier
- INSERM U1082, Poitiers, France.,Department of Digestive Surgery and Liver Transplantation, Trousseau University Hospital, Tours University, Tours, France
| | | | - Ephrem Salamé
- INSERM U1082, Poitiers, France.,Department of Digestive Surgery and Liver Transplantation, Trousseau University Hospital, Tours University, Tours, France
| | - Aurélie Robin
- INSERM U1082, Poitiers University Hospital, Poitiers, France
| | | | - Jean-Marc Gombert
- INSERM U1082, Poitiers, France.,Department of Immunology and Inflammation, Poitiers University Hospital, University of Poitiers, Poitiers, France
| | - Christine Silvain
- Department of Hepatology and Gastroenterology, Poitiers University Hospital, University of Poitiers, Poitiers, France
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35
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Sebode M, Wigger J, Filpe P, Fischer L, Weidemann S, Krech T, Weiler-Normann C, Peiseler M, Hartl J, Tolosa E, Herkel J, Schramm C, Lohse AW, Arrenberg P. Inflammatory Phenotype of Intrahepatic Sulfatide-Reactive Type II NKT Cells in Humans With Autoimmune Hepatitis. Front Immunol 2019; 10:1065. [PMID: 31191516 PMCID: PMC6546815 DOI: 10.3389/fimmu.2019.01065] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2019] [Accepted: 04/25/2019] [Indexed: 01/06/2023] Open
Abstract
Background: Natural Killer T (NKT) cells are CD1d-restricted innate-like T cells that can rapidly release stored cytokines upon recognition of lipid antigens. In mice, type I NKT cells seem to promote liver inflammation, whereas type II NKT cells seem to restrict hepatitis. Here, we aimed at characterizing the role of human type I and type II NKT in patients with autoimmune hepatitis (AIH). Methods: NKT cells were analyzed by flow cytometry in peripheral blood and liver of AIH patients and control groups. α-galactosylceramide-loaded or sulfatide-loaded tetramers were used to detect type I or II NKT cells, respectively. Hepatic CD1d was stained by in situ-hybridization of liver biopsies. Results and Conclusions: Type II NKT cells were more prevalent in human peripheral blood and liver than type I NKT cells. In AIH patients, the frequency of sulfatide-reactive type II NKT cells was significantly increased in peripheral blood (0.11% of peripheral blood leukocytes) and liver (3.78% of intrahepatic leukocytes) compared to healthy individuals (0.05% and 1.82%) and patients with drug-induced liver injury (0.06% and 2.03%; p < 0.05). Intrahepatic type II NKT cells of AIH patients had a different cytokine profile than healthy subjects with an increased frequency of TNFα (77.8% vs. 59.1%, p < 0.05), decreased IFNγ (32.7% vs. 63.0%, p < 0.05) and a complete lack of IL-4 expressing cells (0% vs. 2.1%, p < 0.05). T cells in portal tracts expressed significantly more CD1d-RNA in AIH livers compared to controls. This study supports that in contrast to their assumed protective role in mice, human intrahepatic, sulfatide-reactive type II NKT cells displayed a proinflammatory cytokine profile in patients with AIH. Infiltrating T cells in portal areas of AIH patients overexpressed CD1d and could thereby activate type II NKT cells.
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Affiliation(s)
- Marcial Sebode
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.,European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Hamburg, Germany
| | - Jennifer Wigger
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Pamela Filpe
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Lutz Fischer
- Department of Hepatobiliary Surgery and Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Sören Weidemann
- Department of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Till Krech
- Department of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Christina Weiler-Normann
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.,European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Hamburg, Germany.,Martin Zeitz Center for Rare Diseases, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Moritz Peiseler
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.,European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Hamburg, Germany
| | - Johannes Hartl
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.,European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Hamburg, Germany
| | - Eva Tolosa
- Institute of Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Johannes Herkel
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Christoph Schramm
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.,European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Hamburg, Germany.,Martin Zeitz Center for Rare Diseases, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Ansgar W Lohse
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.,European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Hamburg, Germany
| | - Philomena Arrenberg
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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36
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Zhu H, Zhang Q, Chen G. CXCR6 deficiency ameliorates ischemia-reperfusion injury by reducing the recruitment and cytokine production of hepatic NKT cells in a mouse model of non-alcoholic fatty liver disease. Int Immunopharmacol 2019; 72:224-234. [PMID: 31002999 DOI: 10.1016/j.intimp.2019.04.021] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2018] [Revised: 03/26/2019] [Accepted: 04/08/2019] [Indexed: 12/16/2022]
Abstract
Fatty liver is used for transplantation due to organ shortage, but prone to cause complications like ischemia-reperfusion injury (IRI). NKT cells as a bridge between innate and adaptive immunity were reported to infiltrate the liver at the early phase of IRI induced in normal liver. However, the localization mechanism of NKT cells is not precise, and the role of NKT cells in fatty liver IRI is poorly understood. In present murine IRI model of non-alcoholic fatty liver disease, we demonstrated that although the number reduced in fatty liver, NKT cells still activated and accumulated to fatty liver following IRI, and contributed to IRI by producing inflammatory cytokine IFN-γ. We revealed that NKT cells in fatty liver expressed more CXCR6, a vital chemokine receptor; meanwhile, the ligand CXCL16 mRNA expression level in fatty liver was up-regulated. The up-regulation of the CXCR6/CXCL16 axis in fatty liver happened in IRI, which maybe endow NKT cells more chemotaxis. We further found CXCR6 deficiency reduced the recruitment of NKT cells in a tissue-dependent manner, and impaired the IFN-γ producing capacity of hepatic NKT cells. Serum ALT level and hepatic histology were both improved in CXCR6 deficient mice. The results provide evidence of the pathogenic role of NKT cells in fatty liver IRI, and important localization mechanism involving up-regulated CXCR6/CXCL16. Deficiency of CXCR6 protects the fatty liver from IRI by reducing the recruitment and cytokine production of hepatic NKT cells.
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Affiliation(s)
- Huanbing Zhu
- Department of Hepatic Surgery and Liver Transplantation Center of The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, China; Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States of America.
| | - Qi Zhang
- Department of Hepatic Surgery and Liver Transplantation Center of The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, China
| | - Guihua Chen
- Department of Hepatic Surgery and Liver Transplantation Center of The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, China.
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37
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Kim EY, Oldham WM. Innate T cells in the intensive care unit. Mol Immunol 2019; 105:213-223. [PMID: 30554082 PMCID: PMC6331274 DOI: 10.1016/j.molimm.2018.09.026] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2018] [Revised: 08/22/2018] [Accepted: 09/29/2018] [Indexed: 12/15/2022]
Abstract
Rapid onset of acute inflammation is a hallmark of critical illnesses that bring patients to the intensive care unit (ICU). In critical illness, innate T cells rapidly reach full activation and drive a robust acute inflammatory response. As "cellular adjuvants," innate T cells worsen inflammation and mortality in several common critical illnesses including sepsis, ischemia-reperfusion injury, stroke, and exacerbations of respiratory disease. Interestingly, innate T cell subsets can also promote a protective and anti-inflammatory response in sepsis, ischemia-reperfusion injury, and asthma. Therapies that target innate T cells have been validated in several models of critical illness. Here, we review the role of natural killer T (NKT) cells, mucosal-associated invariant T (MAIT) cells and γδ T cells in clinical and experimental critical illness.
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Affiliation(s)
- Edy Yong Kim
- Brigham and Women's Hospital, Pulmonary and Critical Care Medicine, Boston, MA, 02115, United States; Harvard Medical School, Boston, MA, 02115, United States.
| | - William M Oldham
- Brigham and Women's Hospital, Pulmonary and Critical Care Medicine, Boston, MA, 02115, United States; Harvard Medical School, Boston, MA, 02115, United States
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38
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Activation of natural killer T cells contributes to triptolide-induced liver injury in mice. Acta Pharmacol Sin 2018; 39:1847-1854. [PMID: 30013034 DOI: 10.1038/s41401-018-0084-9] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2018] [Accepted: 06/19/2018] [Indexed: 12/24/2022]
Abstract
Triptolide (TP) is the main active ingredient of Tripterygium wilfordii Hook.f, which has attracted great interest due to its promising efficacy for autoimmune diseases and tumors. However, severe adverse reactions, especially hepatotoxicity, have restricted its approval in the market. In the present study we explored the role of hepatic natural killer T (NKT) cells in the pathogenesis of TP-induced liver injury in mice. TP (600 μg/kg/day, i.g.) was administered to female mice for 1, 3, or 5 days. We found that administration of TP dose-dependently induced hepatotoxicity, evidenced by the body weight reduction, elevated serum ALT and AST levels, as well as significant histopathological changes in the livers. However, the mice were resistant to the development of TP-induced liver injury when their NKT cells were depleted by injection of anti-NK1.1 mAb (200 μg, i.p.) on days -2 and -1 before TP administration. We further revealed that TP administration activated NKT cells, dominantly releasing Th1 cytokine IFN-γ, recruiting neutrophils and macrophages, and leading to liver damage. After anti-NK1.1 injection, however, the mice mainly secreted Th2 cytokine IL-4 in the livers and exhibited a significantly lower percentage of hepatic infiltrating neutrophils and macrophages upon TP challenge. The activation of NKT cells was associated with the upregulation of Toll-like receptor (TLR) signaling pathway. Collectively, these results demonstrate a novel role of NKT cells contributing to the mechanisms of TP-induced liver injury. More importantly, the regulation of NKT cells may promote effective measures that control drug-induced liver injury.
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39
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Maricic I, Marrero I, Eguchi A, Nakamura R, Johnson CD, Dasgupta S, Hernandez CD, Nguyen PS, Swafford AD, Knight R, Feldstein AE, Loomba R, Kumar V. Differential Activation of Hepatic Invariant NKT Cell Subsets Plays a Key Role in Progression of Nonalcoholic Steatohepatitis. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2018; 201:3017-3035. [PMID: 30322964 PMCID: PMC6219905 DOI: 10.4049/jimmunol.1800614] [Citation(s) in RCA: 77] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/01/2018] [Accepted: 09/07/2018] [Indexed: 02/07/2023]
Abstract
Innate immune mechanisms play an important role in inflammatory chronic liver diseases. In this study, we investigated the role of type I or invariant NKT (iNKT) cell subsets in the progression of nonalcoholic steatohepatitis (NASH). We used α-galactosylceramide/CD1d tetramers and clonotypic mAb together with intracytoplasmic cytokine staining to analyze iNKT cells in choline-deficient l-amino acid-defined (CDAA)-induced murine NASH model and in human PBMCs, respectively. Cytokine secretion of hepatic iNKT cells in CDAA-fed C57BL/6 mice altered from predominantly IL-17+ to IFN-γ+ and IL-4+ during NASH progression along with the downmodulation of TCR and NK1.1 expression. Importantly, steatosis, steatohepatitis, and fibrosis were dependent upon the presence of iNKT cells. Hepatic stellate cell activation and infiltration of neutrophils, Kupffer cells, and CD8+ T cells as well as expression of key proinflammatory and fibrogenic genes were significantly blunted in Jα18-/- mice and in C57BL/6 mice treated with an iNKT-inhibitory RAR-γ agonist. Gut microbial diversity was significantly impacted in Jα18-/- and in CDAA diet-fed mice. An increased frequency of CXCR3+IFN-γ+T-bet+ and IL-17A+ iNKT cells was found in PBMC from NASH patients in comparison with nonalcoholic fatty liver patients or healthy controls. Consistent with their in vivo activation, iNKT cells from NASH patients remained hyporesponsive to ex-vivo stimulation with α-galactosylceramide. Accumulation of plasmacytoid dendritic cells in both mice and NASH patients suggest their role in activation of iNKT cells. In summary, our findings indicate that the differential activation of iNKT cells play a key role in mediating diet-induced hepatic steatosis and fibrosis in mice and its potential involvement in NASH progression in humans.
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Affiliation(s)
- Igor Maricic
- Division of Gastroenterology, Department of Medicine, University of California San Diego, La Jolla, CA 92093
| | - Idania Marrero
- Division of Gastroenterology, Department of Medicine, University of California San Diego, La Jolla, CA 92093
| | - Akiko Eguchi
- Department of Pediatrics, University of California San Diego, La Jolla, CA 92093
| | - Ryota Nakamura
- Department of Pediatrics, University of California San Diego, La Jolla, CA 92093
| | - Casey D Johnson
- Department of Pediatrics, University of California San Diego, La Jolla, CA 92093
| | - Suryasarathi Dasgupta
- Division of Gastroenterology, Department of Medicine, University of California San Diego, La Jolla, CA 92093
| | - Carolyn D Hernandez
- Division of Gastroenterology, Department of Medicine, University of California San Diego, La Jolla, CA 92093
| | - Phirum Sam Nguyen
- Division of Gastroenterology, Department of Medicine, University of California San Diego, La Jolla, CA 92093
| | - Austin D Swafford
- Center for Microbiome Innovation, University of California San Diego, La Jolla, CA 92093
| | - Rob Knight
- Department of Pediatrics, University of California San Diego, La Jolla, CA 92093
- Center for Microbiome Innovation, University of California San Diego, La Jolla, CA 92093
- Department of Computer Science and Engineering, University of California San Diego, La Jolla, CA 92093; and
| | - Ariel E Feldstein
- Department of Pediatrics, University of California San Diego, La Jolla, CA 92093
- Nonalcoholic Fatty Liver Disease Research Center, University of California San Diego, La Jolla, CA 92093
| | - Rohit Loomba
- Division of Gastroenterology, Department of Medicine, University of California San Diego, La Jolla, CA 92093
- Center for Microbiome Innovation, University of California San Diego, La Jolla, CA 92093
- Nonalcoholic Fatty Liver Disease Research Center, University of California San Diego, La Jolla, CA 92093
| | - Vipin Kumar
- Division of Gastroenterology, Department of Medicine, University of California San Diego, La Jolla, CA 92093;
- Center for Microbiome Innovation, University of California San Diego, La Jolla, CA 92093
- Nonalcoholic Fatty Liver Disease Research Center, University of California San Diego, La Jolla, CA 92093
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40
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Huang W, He W, Shi X, He X, Dou L, Gao Y. The Role of CD1d and MR1 Restricted T Cells in the Liver. Front Immunol 2018; 9:2424. [PMID: 30425710 PMCID: PMC6218621 DOI: 10.3389/fimmu.2018.02424] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2018] [Accepted: 10/01/2018] [Indexed: 12/17/2022] Open
Abstract
The liver is one of the most important immunological organs that remains tolerogenic in homeostasis yet promotes rapid responses to pathogens in the presence of a systemic infection. The composition of leucocytes in the liver is highly distinct from that of the blood and other lymphoid organs, particularly with respect to enrichment of innate T cells, i.e., invariant NKT cells (iNKT cells) and Mucosal-Associated Invariant T cells (MAIT cells). In recent years, studies have revealed insights into their biology and potential roles in maintaining the immune-environment in the liver. As the primary liver-resident immune cells, they are emerging as significant players in the human immune system and are associated with an increasing number of clinical diseases. As such, innate T cells are promising targets for modifying host defense and inflammation of various liver diseases, including viral, autoimmune, and those of tumor origin. In this review, we emphasize and discuss some of the recent discoveries and advances in the biology of innate T cells, their recruitment and diversity in the liver, and their role in various liver diseases, postulating on their potential application in immunotherapy.
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Affiliation(s)
- Wenyong Huang
- Organ Transplantation Unit, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Wenjing He
- Organ Transplantation Unit, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Xiaomin Shi
- Organ Transplantation Unit, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Xiaoshun He
- Organ Transplantation Unit, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Lang Dou
- Organ Transplantation Unit, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yifang Gao
- Organ Transplantation Unit, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
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41
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Ferhat MH, Robin A, Barbier L, Thierry A, Gombert JM, Barbarin A, Herbelin A. The Impact of Invariant NKT Cells in Sterile Inflammation: The Possible Contribution of the Alarmin/Cytokine IL-33. Front Immunol 2018; 9:2308. [PMID: 30374349 PMCID: PMC6197076 DOI: 10.3389/fimmu.2018.02308] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2018] [Accepted: 09/17/2018] [Indexed: 01/13/2023] Open
Abstract
Although the contribution of iNKT cells to induction of sterile inflammation is now well-established, the nature of the endogenous compounds released early after cellular stress or damage that drive their activation and recruitment remains poorly understood. More precisely, iNKT cells have not been described as being reactive to endogenous non-protein damage-associated molecular-pattern molecules (DAMPs). A second subset of DAMPs, called alarmins, are tissue-derived nuclear proteins, constitutively expressed at high levels in epithelial barrier tissues and endothelial barriers. These potent immunostimulants, immediately released after tissue damage, include the alarmin IL-33. This factor has aroused interest due to its singular action as an alarmin during infectious, allergic responses and acute tissue injury, and as a cytokine, contributing to the latter resolutive/repair phase of sterile inflammation. IL-33 targets iNKT cells, inducing their recruitment in an inflammatory state, and amplifying their regulatory and effector functions. In the present review, we introduce the new concept of a biological axis of iNKT cells and IL-33, involved in alerting and controlling the immune cells in experimental models of sterile inflammation. This review will focus on acute organ injury models, especially ischemia-reperfusion injury, in the kidneys, liver and lungs, where iNKT cells and IL-33 have been presumed to mediate and/or control the injury mechanisms, and their potential relevance in human pathophysiology.
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Affiliation(s)
| | | | - Louise Barbier
- Service de Chirurgie Digestive, Oncologique, Endocrinienne et Transplantation Hépatique, CHU Trousseau, Université de Tours, Tours, France
| | - Antoine Thierry
- INSERM U1082 - IRATI Group, Poitiers, France.,Service de Néphrologie, Hémodialyse et Transplantation Rénale, CHU de Poitiers, Poitiers, France
| | - Jean-Marc Gombert
- INSERM U1082 - IRATI Group, Poitiers, France.,Service d'Immunologie et d'Inflammation, CHU de Poitiers, Poitiers, France
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42
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Marrero I, Maricic I, Feldstein AE, Loomba R, Schnabl B, Rivera-Nieves J, Eckmann L, Kumar V. Complex Network of NKT Cell Subsets Controls Immune Homeostasis in Liver and Gut. Front Immunol 2018; 9:2082. [PMID: 30254647 PMCID: PMC6141878 DOI: 10.3389/fimmu.2018.02082] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2018] [Accepted: 08/22/2018] [Indexed: 12/23/2022] Open
Abstract
The liver-gut immune axis is enriched in several innate immune cells, including innate-like unconventional and adaptive T cells that are thought to be involved in the maintenance of tolerance to gut-derived antigens and, at the same time, enable effective immunity against microbes. Two subsets of lipid-reactive CD1d-restricted natural killer T (NKT) cells, invariant NKT (iNKT) and type II NKT cells present in both mice and humans. NKT cells play an important role in regulation of inflammation in the liver and gut due to their innate-like properties of rapid secretion of a myriad of pro-inflammatory and anti-inflammatory cytokines and their ability to influence other innate cells as well as adaptive T and B cells. Notably, a bi-directional interactive network between NKT cells and gut commensal microbiota plays a crucial role in this process. Here, we briefly review recent studies related to the cross-regulation of both NKT cell subsets and how their interactions with other immune cells and parenchymal cells, including hepatocytes and enterocytes, control inflammatory diseases in the liver, such as alcoholic and non-alcoholic steatohepatitis, as well as inflammation in the gut. Overwhelming experimental data suggest that while iNKT cells are pathogenic, type II NKT cells are protective in the liver. Since CD1d-dependent pathways are highly conserved from mice to humans, a detailed cellular and molecular understanding of these immune regulatory pathways will have major implications for the development of novel therapeutics against inflammatory diseases of liver and gut.
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Affiliation(s)
- Idania Marrero
- Laboratory of Immune Regulation, University of California, San Diego, La Jolla, CA, United States.,Division of Gastroenterology and Hepatology, Department of Medicine, University of California, San Diego, La Jolla, CA, United States
| | - Igor Maricic
- Laboratory of Immune Regulation, University of California, San Diego, La Jolla, CA, United States.,Division of Gastroenterology and Hepatology, Department of Medicine, University of California, San Diego, La Jolla, CA, United States
| | - Ariel E Feldstein
- Department of Pediatrics, University of California, San Diego, La Jolla, CA, United States
| | - Rohit Loomba
- Division of Gastroenterology and Hepatology, Department of Medicine, University of California, San Diego, La Jolla, CA, United States
| | - Bernd Schnabl
- Division of Gastroenterology and Hepatology, Department of Medicine, University of California, San Diego, La Jolla, CA, United States
| | - Jesus Rivera-Nieves
- Division of Gastroenterology and Hepatology, Department of Medicine, University of California, San Diego, La Jolla, CA, United States
| | - Lars Eckmann
- Division of Gastroenterology and Hepatology, Department of Medicine, University of California, San Diego, La Jolla, CA, United States
| | - Vipin Kumar
- Laboratory of Immune Regulation, University of California, San Diego, La Jolla, CA, United States.,Division of Gastroenterology and Hepatology, Department of Medicine, University of California, San Diego, La Jolla, CA, United States
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43
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Singh AK, Tripathi P, Cardell SL. Type II NKT Cells: An Elusive Population With Immunoregulatory Properties. Front Immunol 2018; 9:1969. [PMID: 30210505 PMCID: PMC6120993 DOI: 10.3389/fimmu.2018.01969] [Citation(s) in RCA: 71] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2018] [Accepted: 08/10/2018] [Indexed: 12/20/2022] Open
Abstract
Natural killer T (NKT) cells are unique unconventional T cells that are reactive to lipid antigens presented on the non-polymorphic major histocompatibility class (MHC) I-like molecule CD1d. They have characteristics of both innate and adaptive immune cells, and have potent immunoregulatory roles in tumor immunity, autoimmunity, and infectious diseases. Based on their T cell receptor (TCR) expression, NKT cells are divided into two subsets, type I NKT cells with an invariant TCRα-chain (Vα24 in humans, Vα14 in mice) and type II NKT cells with diverse TCRs. While type I NKT cells are well-studied, knowledge about type II NKT cells is still limited, and it is to date only possible to identify subsets of this population. However, recent advances have shown that both type I and type II NKT cells play important roles in many inflammatory situations, and can sometimes regulate the functions of each other. Type II NKT cells can be both protective and pathogenic. Here, we review current knowledge on type II NKT cells and their functions in different disease settings and how these cells can influence immunological outcomes.
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Affiliation(s)
- Avadhesh Kumar Singh
- Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Prabhanshu Tripathi
- Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Susanna L Cardell
- Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
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44
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Lu TF, Yang TH, Zhong CP, Shen C, Lin WW, Gu GX, Xia Q, Xu N. Dual Effect of Hepatic Macrophages on Liver Ischemia and Reperfusion Injury during Liver Transplantation. Immune Netw 2018; 18:e24. [PMID: 29984042 PMCID: PMC6026692 DOI: 10.4110/in.2018.18.e24] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2018] [Revised: 06/20/2018] [Accepted: 06/21/2018] [Indexed: 12/14/2022] Open
Abstract
Ischemia-reperfusion injury (IRI) is a major complication in liver transplantation (LT) and it is closely related to the recovery of grafts' function. Researches has verified that both innate and adaptive immune system are involved in the development of IRI and Kupffer cell (KC), the resident macrophages in the liver, play a pivotal role both in triggering and sustaining the sterile inflammation. Damage-associated molecular patterns (DAMPs), released by the initial dead cell because of the ischemia insult, firstly activate the KC through pattern recognition receptors (PRRs) such as toll-like receptors. Activated KCs is the dominant players in the IRI as it can secret various pro-inflammatory cytokines to exacerbate the injury and recruit other types of immune cells from the circulation. On the other hand, KCs can also serve in a contrary way to ameliorate IRI by upregulating the anti-inflammatory factors. Moreover, new standpoint has been put forward that KCs and macrophages from the circulation may function in different way to influence the inflammation. Managements towards KCs are expected to be the effective way to improve the IRI.
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Affiliation(s)
- Tian-Fei Lu
- Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
| | - Tai-Hua Yang
- Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medicine School, Hannover 30625, Germany
| | - Cheng-Peng Zhong
- Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
| | - Chuan Shen
- Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
| | - Wei-Wei Lin
- Department of Laboratory, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
| | - Guang-Xiang Gu
- Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
| | - Qiang Xia
- Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
| | - Ning Xu
- Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
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45
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The Role of Invariant NKT in Autoimmune Liver Disease: Can Vitamin D Act as an Immunomodulator? Can J Gastroenterol Hepatol 2018; 2018:8197937. [PMID: 30046564 PMCID: PMC6038587 DOI: 10.1155/2018/8197937] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2018] [Accepted: 05/16/2018] [Indexed: 12/18/2022] Open
Abstract
Natural killer T (NKT) cells are a distinct lineage of T cells which express both the T cell receptor (TCR) and natural killer (NK) cell markers. Invariant NKT (iNKT) cells bear an invariant TCR and recognize a small variety of glycolipid antigens presented by CD1d (nonclassical MHC-I). CD1d-restricted iNKT cells are regulators of immune responses and produce cytokines that may be proinflammatory (such as interferon-gamma (IFN-γ)) or anti-inflammatory (such as IL-4). iNKT cells also appear to play a role in B cell regulation and antibody production. Alpha-galactosylceramide (α-GalCer), a derivative of the marine sponge, is a potent stimulator of iNKT cells and has been proposed as a therapeutic iNKT cell activator. Invariant NKT cells have been implicated in the development and perpetuation of several autoimmune diseases such as multiple sclerosis and systemic lupus erythematosus (SLE). Animal models of SLE have shown abnormalities in iNKT cells numbers and function, and an inverse correlation between the frequency of NKT cells and IgG levels has also been observed. The role of iNKT cells in autoimmune liver disease (AiLD) has not been extensively studied. This review discusses the current data with regard to iNKT cells function in AiLD, in addition to providing an overview of iNKT cells function in other autoimmune conditions and animal models. We also discuss data regarding the immunomodulatory effects of vitamin D on iNKT cells, which may serve as a potential therapeutic target, given that deficiencies in vitamin D have been reported in various autoimmune disorders.
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46
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Nishioka Y, Masuda S, Tomaru U, Ishizu A. CD1d-Restricted Type II NKT Cells Reactive With Endogenous Hydrophobic Peptides. Front Immunol 2018; 9:548. [PMID: 29599785 PMCID: PMC5862807 DOI: 10.3389/fimmu.2018.00548] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2017] [Accepted: 03/05/2018] [Indexed: 11/13/2022] Open
Abstract
NKT cells belong to a distinct subset of T cells that recognize hydrophobic antigens presented by major histocompatibility complex class I-like molecules, such as CD1d. Because NKT cells stimulated by antigens can activate or suppress other immunocompetent cells through an immediate production of a large amount of cytokines, they are regarded as immunological modulators. CD1d-restricted NKT cells are classified into two subsets, namely, type I and type II. CD1d-restricted type I NKT cells express invariant T cell receptors (TCRs) and react with lipid antigens, including the marine sponge-derived glycolipid α-galactosylceramide. On the contrary, CD1d-restricted type II NKT cells recognize a wide variety of antigens, including glycolipids, phospholipids, and hydrophobic peptides, by their diverse TCRs. In this review, we focus particularly on CD1d-restricted type II NKT cells that recognize endogenous hydrophobic peptides presented by CD1d. Previous studies have demonstrated that CD1d-restricted type I NKT cells usually act as pro-inflammatory cells but sometimes behave as anti-inflammatory cells. It has been also demonstrated that CD1d-restricted type II NKT cells play opposite roles to CD1d-restricted type I NKT cells; thus, they function as anti-inflammatory or pro-inflammatory cells depending on the situation. In line with this, CD1d-restricted type II NKT cells that recognize type II collagen peptide have been demonstrated to act as anti-inflammatory cells in diverse inflammation-induction models in mice, whereas pro-inflammatory CD1d-restricted type II NKT cells reactive with sterol carrier protein 2 peptide have been demonstrated to be involved in the development of small vessel vasculitis in rats.
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Affiliation(s)
- Yusuke Nishioka
- Graduate School of Health Sciences, Hokkaido University, Sapporo, Japan
| | - Sakiko Masuda
- Faculty of Health Sciences, Hokkaido University, Sapporo, Japan
| | - Utano Tomaru
- Department of Pathology, Faculty of Medicine, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Akihiro Ishizu
- Faculty of Health Sciences, Hokkaido University, Sapporo, Japan
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47
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Ware R, Kumar V. Complexity and function of natural killer T cells with potential application to hepatic transplant survival. Liver Transpl 2017; 23:1589-1592. [PMID: 28945950 PMCID: PMC6075735 DOI: 10.1002/lt.24950] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2017] [Revised: 08/10/2017] [Accepted: 08/27/2017] [Indexed: 12/12/2022]
Abstract
One of the major innate-like lymphocyte populations enriched in the liver consists of natural killer T (NKT) cells, which recognize self and foreign lipid antigens presented by the nonpolymorphic class I major histocompatibility complex-like molecule CD1d. NKT cells express natural killer cell markers as well as T cell receptors (TCRs) and can be classified into 2 categories: type I NKT cells use a semi-invariant TCR, whereas type II NKT cells express diverse but still limited TCRs. An emerging body of evidence points to their opposing roles in inflammation, including ischemia/reperfusion injury. Improved understanding of their roles in experimental models as well as in humans and the means by which their function can be manipulated may provide therapeutic benefit in liver diseases and in organ transplantation. Liver Transplantation 23 1589-1592 2017 AASLD.
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Affiliation(s)
- Randle Ware
- Laboratory of Immune Regulation, Department of Medicine; University of California, San Diego; La Jolla CA
| | - Vipin Kumar
- Laboratory of Immune Regulation, Department of Medicine; University of California, San Diego; La Jolla CA
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48
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van Puijvelde GH, Kuiper J. NKT cells in cardiovascular diseases. Eur J Pharmacol 2017; 816:47-57. [DOI: 10.1016/j.ejphar.2017.03.052] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2016] [Revised: 03/10/2017] [Accepted: 03/23/2017] [Indexed: 12/17/2022]
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49
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Natural killer T cells in Preeclampsia: An updated review. Biomed Pharmacother 2017; 95:412-418. [DOI: 10.1016/j.biopha.2017.08.077] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2017] [Revised: 08/19/2017] [Accepted: 08/19/2017] [Indexed: 12/13/2022] Open
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50
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Dhodapkar MV, Kumar V. Type II NKT Cells and Their Emerging Role in Health and Disease. THE JOURNAL OF IMMUNOLOGY 2017; 198:1015-1021. [PMID: 28115591 DOI: 10.4049/jimmunol.1601399] [Citation(s) in RCA: 91] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/11/2016] [Accepted: 11/11/2016] [Indexed: 12/11/2022]
Abstract
NKT cells recognize lipid Ags presented by a class I MHC-like molecule CD1d, a member of the CD1 family. Although most initial studies on NKT cells focused on a subset with semi-invariant TCR termed invariant NKT cells, the majority of CD1d-restricted lipid-reactive human T cells express diverse TCRs and are termed type II NKT cells. These cells constitute a distinct population of circulating and tissue-resident effector T cells with immune-regulatory properties. They react to a growing list of self- as well as non-self-lipid ligands, and share some properties with both invariant NKT and conventional T cells. An emerging body of evidence points to their role in the regulation of immunity to pathogens/tumors and in autoimmune/metabolic disorders. An improved understanding of the biology of these cells and the ability to manipulate their function may be of therapeutic benefit in diverse disease conditions.
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Affiliation(s)
- Madhav V Dhodapkar
- Section of Hematology, Department of Medicine, Yale School of Medicine, Yale University, New Haven CT 06510; .,Department of Immunobiology, Yale School of Medicine, Yale University, New Haven CT 06510.,Yale Cancer Center, Yale School of Medicine, Yale University, New Haven, CT 06510; and
| | - Vipin Kumar
- Department of Medicine, University of California, San Diego, La Jolla, CA 92037
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