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Sakaguchi T, Nagahama Y, Hamada N, Singh SK, Mikami H, Maeda K, Akira S. Novel Choline-Deficient and 0.1%-Methionine-Added High-Fat Diet Induces Burned-Out Metabolic-Dysfunction-Associated Steatohepatitis with Inflammation by Rapid Immune Cell Infiltration on Male Mice. Nutrients 2024; 16:4151. [PMID: 39683544 DOI: 10.3390/nu16234151] [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: 11/01/2024] [Revised: 11/26/2024] [Accepted: 11/27/2024] [Indexed: 12/18/2024] Open
Abstract
Background: Metabolic-dysfunction-associated steatotic liver disease (MASLD) is a progressive liver disorder that possesses metabolic dysfunction and shows steatohepatitis. Although the number of patients is globally increasing and many clinical studies have developed medicine for MASLD, most of the studies have failed due to low efficacy. One reason for this failure is the lack of appropriate animal disease models that reflect human MASLD to evaluate the potency of candidate drugs. Methods: We developed a novel choline-deficient and 0.11%-methionine-added high-fat diet (CDAHFD)-based (MASH) diet that can induce murine metabolic-dysfunction-associated steatohepatitis (MASH) without severe body weight loss. We performed kinetic analyses post-feeding and proposed an appropriate timing of MASH pathogenesis by quantitatively analyzing steatosis, inflammation, and fibrosis. Results: This MASH diet induced liver fibrosis earlier than the conventional CDAHFD model. In brief, lipid accumulation, inflammation, and fibrosis started after 1 week from feeding. Lipid accumulation increased until 8 weeks and declined thereafter; on the other hand, liver fibrosis showed continuous progression. Additionally, immune cells, especially myeloid cells, specifically accumulated and induced inflammation in the initiation stage of MASH. Conclusions: The novel MASH diet promotes the dynamics of lipid deposition and fibrosis in the liver, similar to human MASH pathophysiology. Furthermore, immune-cell-derived inflammation possibly contributes to the initiation of MASH pathogenesis. We propose this model can be the new pre-clinical MASH model to discover the drugs against human MASH by evaluating the interaction between parenchymal and non-parenchymal cells.
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Affiliation(s)
- Takatoshi Sakaguchi
- Laboratory of Host Defense, Immunology Frontier Research Center, Osaka University, Suita 565-0871, Japan
| | - Yasuharu Nagahama
- Laboratory of Host Defense, Immunology Frontier Research Center, Osaka University, Suita 565-0871, Japan
- Host Defense Laboratory, Immunology Unit, Osaka Research Center for Drug Discovery, Otsuka Pharmaceutical Co., Ltd., Minoh 562-0029, Japan
| | - Nanako Hamada
- Laboratory of Host Defense, Immunology Frontier Research Center, Osaka University, Suita 565-0871, Japan
| | - Shailendra Kumar Singh
- Laboratory of Host Defense, Immunology Frontier Research Center, Osaka University, Suita 565-0871, Japan
| | | | - Kazuhiko Maeda
- Laboratory of Host Defense, Immunology Frontier Research Center, Osaka University, Suita 565-0871, Japan
- Department of Host Defense, Research Institute for Microbial Diseases (RIMD), Osaka University, Suita 565-0871, Japan
| | - Shizuo Akira
- Laboratory of Host Defense, Immunology Frontier Research Center, Osaka University, Suita 565-0871, Japan
- Department of Host Defense, Research Institute for Microbial Diseases (RIMD), Osaka University, Suita 565-0871, Japan
- Center for Advanced Modalities and Drug Delivery System (CAMaD), Osaka University, Suita 565-0871, Japan
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Cloutier M, Variya B, Akbari SA, Rexhepi F, Ilangumaran S, Ramanathan S. Profibrogenic role of IL-15 through IL-15 receptor alpha-mediated trans-presentation in the carbon tetrachloride-induced liver fibrosis model. Front Immunol 2024; 15:1404891. [PMID: 38919611 PMCID: PMC11196400 DOI: 10.3389/fimmu.2024.1404891] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2024] [Accepted: 05/22/2024] [Indexed: 06/27/2024] Open
Abstract
Background Inflammatory cytokines play key pathogenic roles in liver fibrosis. IL-15 is a proinflammatory cytokine produced by myeloid cells. IL-15 promotes pathogenesis of several chronic inflammatory diseases. However, increased liver fibrosis has been reported in mice lacking IL-15 receptor alpha chain (IL-15Rα), suggesting an anti-fibrogenic role for IL-15. As myeloid cells are key players in liver fibrosis and IL-15 signaling can occur independently of IL-15Rα, we investigated the requirement of IL-15 and IL-15Rα in liver fibrosis. Methods We induced liver fibrosis in Il15-/- , Il15ra-/- and wildtype C57BL/6 mice by the administration of carbon tetrachloride (CCl4). Liver fibrosis was evaluated by Sirius red and Mason's trichrome staining and α-smooth muscle acting immunostaining of myofibroblasts. Gene expression of collagens, matrix modifying enzymes, cytokines and chemokines was quantified by RT-qPCR. The phenotype and the numbers of intrahepatic lymphoid and myeloid cell subsets were evaluated by flow cytometry. Results Both Il15-/- and Il15ra-/- mice developed markedly reduced liver fibrosis compared to wildtype control mice, as revealed by reduced collagen deposition and myofibroblast content. Il15ra-/- mice showed further reduction in collagen deposition compared to Il15-/- mice. However, Col1a1 and Col1a3 genes were similarly induced in the fibrotic livers of wildtype, Il15-/- and Il15ra-/- mice, although notable variations were observed in the expression of matrix remodeling enzymes and chemokines. As expected, Il15-/- and Il15ra-/- mice showed markedly reduced numbers of NK cells compared to wildtype mice. They also showed markedly less staining of CD45+ immune cells and CD68+ macrophages, and significantly reduced inflammatory cell infiltration into the liver, with fewer pro-inflammatory and anti-inflammatory monocyte subsets compared to wildtype mice. Conclusion Our findings indicate that IL-15 exerts its profibrogenic role in the liver by promoting macrophage activation and that this requires trans-presentation of IL-15 by IL-15Rα.
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Li J, Zhang Y, Li H, Jiang J, Guo C, Zhou Z, Luo Y, Zhou C, Ming Y. Single-cell RNA sequencing reveals a peripheral landscape of immune cells in Schistosomiasis japonica. Parasit Vectors 2023; 16:356. [PMID: 37817226 PMCID: PMC10563327 DOI: 10.1186/s13071-023-05975-y] [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: 06/27/2023] [Accepted: 09/20/2023] [Indexed: 10/12/2023] Open
Abstract
BACKGROUND Schistosomiasis, also known as bilharzia, is a devastating parasitic disease. This progressive and debilitating helminth disease is often associated with poverty and can lead to chronic poor health. Despite ongoing research, there is currently no effective vaccine for schistosomiasis, and praziquantel remains the only available treatment option. According to the progression of schistosomiasis, infections caused by schistosomes are classified into three distinct clinical phases: acute, chronic and advanced schistosomiasis. However, the underlying immune mechanism involved in the progression of schistosomiasis remains poorly understood. METHODS We employed single-cell RNA sequencing (scRNA-seq) to profile the immune landscape of Schistosomiasis japonica infection based on peripheral blood mononuclear cells (PBMCs) from a healthy control group (n = 4), chronic schistosomiasis group (n = 4) and advanced schistosomiasis group (n = 2). RESULTS Of 89,896 cells, 24 major cell clusters were ultimately included in our analysis. Neutrophils and NK/T cells accounted for the major proportion in the chronic group and the healthy group, and monocytes dominated in the advanced group. A preliminary study showed that NKT cells were increased in patients with schistosomiasis and that CXCR2 + NKT cells were proinflammatory cells. Plasma cells also accounted for a large proportion of B cells in the advanced group. MHC molecules in monocytes were notably lower in the advanced group than in the chronic group or the healthy control group. However, monocytes in the advanced group exhibited high expression of FOLR3 and CCR2. CONCLUSIONS Overall, this study enhances our understanding of the immune mechanisms involved in schistosomiasis. It provides a transcriptional atlas of peripheral immune cells that may contribute to elimination of the disease. This preliminary study suggests that the increased presence of CCR2 + monocyte and CXCR2 + NKT cells might participate in the progression of schistosomiasis.
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Affiliation(s)
- Junhui Li
- Transplantation Center, The Third Xiangya Hospital, Central South University, No. 138 Tongzipo Road, Changsha, 410013, Hunan, China
- Engineering and Technology Research Center for Transplantation Medicine of National Health Commission, Changsha, Hunan, China
| | - Yu Zhang
- Transplantation Center, The Third Xiangya Hospital, Central South University, No. 138 Tongzipo Road, Changsha, 410013, Hunan, China
- Engineering and Technology Research Center for Transplantation Medicine of National Health Commission, Changsha, Hunan, China
| | - Hao Li
- Transplantation Center, The Third Xiangya Hospital, Central South University, No. 138 Tongzipo Road, Changsha, 410013, Hunan, China
- Engineering and Technology Research Center for Transplantation Medicine of National Health Commission, Changsha, Hunan, China
| | - Jie Jiang
- Transplantation Center, The Third Xiangya Hospital, Central South University, No. 138 Tongzipo Road, Changsha, 410013, Hunan, China
- Engineering and Technology Research Center for Transplantation Medicine of National Health Commission, Changsha, Hunan, China
| | - Chen Guo
- Transplantation Center, The Third Xiangya Hospital, Central South University, No. 138 Tongzipo Road, Changsha, 410013, Hunan, China
- Engineering and Technology Research Center for Transplantation Medicine of National Health Commission, Changsha, Hunan, China
| | - Zhaoqin Zhou
- Transplantation Center, The Third Xiangya Hospital, Central South University, No. 138 Tongzipo Road, Changsha, 410013, Hunan, China
- Engineering and Technology Research Center for Transplantation Medicine of National Health Commission, Changsha, Hunan, China
| | - Yulin Luo
- Transplantation Center, The Third Xiangya Hospital, Central South University, No. 138 Tongzipo Road, Changsha, 410013, Hunan, China
- Engineering and Technology Research Center for Transplantation Medicine of National Health Commission, Changsha, Hunan, China
| | - Chen Zhou
- Transplantation Center, The Third Xiangya Hospital, Central South University, No. 138 Tongzipo Road, Changsha, 410013, Hunan, China
- Engineering and Technology Research Center for Transplantation Medicine of National Health Commission, Changsha, Hunan, China
| | - Yingzi Ming
- Transplantation Center, The Third Xiangya Hospital, Central South University, No. 138 Tongzipo Road, Changsha, 410013, Hunan, China.
- Engineering and Technology Research Center for Transplantation Medicine of National Health Commission, Changsha, Hunan, China.
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Baraka K, Abozahra RR, Badr E, Abdelhamid SM. Study of some potential biomarkers in Egyptian hepatitis C virus patients in relation to liver disease progression and HCC. BMC Cancer 2023; 23:938. [PMID: 37798688 PMCID: PMC10552374 DOI: 10.1186/s12885-023-11420-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2023] [Accepted: 09/19/2023] [Indexed: 10/07/2023] Open
Abstract
BACKGROUND Egypt has the greatest prevalence of hepatitis C worldwide according to the WHO reports, accounting for 13% of the global HCV infections. HCV is a substantial precursor for fibrosis, cirrhosis, and hepatocellular carcinoma. This study aimed to investigate the potential relevance of some cytokines, miR-122 and miR-221 for the diagnosis of liver disease progression associated to HCV infection. METHODS One hundred and twenty blood samples were collected from patients with chronic liver disease, HCC, and healthy individuals. Total bilirubin, alanine aminotransferase, aspartate aminotransferase, platelet count, albumin, and creatinine were measured. Serum level of selected cytokines was conducted by ELISA. Serum miRNA expression was detected by RT-PCR. RESULTS IL-2R was higher among HCC patients and the mean concentration of both TNF-αRII and IL-6R was higher among cirrhotic patients. The expression of miRNA-122 showed a little fold decrease in all studied groups; the highest level was observed in HCC patients. The expression of miRNA-221 showed a significant fold increase in HCC and cirrhotic groups. CONCLUSIONS This study revealed that there is no difference in liver disease progression in patients regarding sex and age. Routine liver function tests performed poorly in terms of early diagnosis of liver disease progression; however, serum total bilirubin gave somewhat useful guide for discrimination between fibrotic, cirrhotic and HCC cases. IL-2R showed a significant consistent increase in its level with disease progression. The miR-221 serum level showed significant fold increase with liver disease progression. Therefore, making miR-221 a potential non-invasive biomarker for liver disease progression in the diagnostic setting is recommended.
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Affiliation(s)
- Kholoud Baraka
- Microbiology and Immunology Department, Faculty of Pharmacy, Damanhour University, El Gomhoreya Street, Damanhour, El Behira Egypt
| | - Rania R. Abozahra
- Microbiology and Immunology Department, Faculty of Pharmacy, Damanhour University, El Gomhoreya Street, Damanhour, El Behira Egypt
| | - Eman Badr
- Microbiology and Immunology Department, Faculty of Pharmacy, Damanhour University, El Gomhoreya Street, Damanhour, El Behira Egypt
| | - Sarah M. Abdelhamid
- Microbiology and Immunology Department, Faculty of Pharmacy, Damanhour University, El Gomhoreya Street, Damanhour, El Behira Egypt
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Abstract
Chronic liver diseases such as nonalcoholic fatty liver disease (NAFLD) or viral hepatitis are characterized by persistent inflammation and subsequent liver fibrosis. Liver fibrosis critically determines long-term morbidity (for example, cirrhosis or liver cancer) and mortality in NAFLD and nonalcoholic steatohepatitis (NASH). Inflammation represents the concerted response of various hepatic cell types to hepatocellular death and inflammatory signals, which are related to intrahepatic injury pathways or extrahepatic mediators from the gut-liver axis and the circulation. Single-cell technologies have revealed the heterogeneity of immune cell activation concerning disease states and the spatial organization within the liver, including resident and recruited macrophages, neutrophils as mediators of tissue repair, auto-aggressive features of T cells as well as various innate lymphoid cell and unconventional T cell populations. Inflammatory responses drive the activation of hepatic stellate cells (HSCs), and HSC subsets, in turn, modulate immune mechanisms via chemokines and cytokines or transdifferentiate into matrix-producing myofibroblasts. Current advances in understanding the pathogenesis of inflammation and fibrosis in the liver, mainly focused on NAFLD or NASH owing to the high unmet medical need, have led to the identification of several therapeutic targets. In this Review, we summarize the inflammatory mediators and cells in the diseased liver, fibrogenic pathways and their therapeutic implications.
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Affiliation(s)
- Linda Hammerich
- Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum and Campus Charité Mitte, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Frank Tacke
- Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum and Campus Charité Mitte, Charité - Universitätsmedizin Berlin, Berlin, Germany.
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Bao N, Fu B, Zhong X, Jia S, Ren Z, Wang H, Wang W, Shi H, Li J, Ge F, Chang Q, Gong Y, Liu W, Qiu F, Xu S, Li T. Role of the CXCR6/CXCL16 axis in autoimmune diseases. Int Immunopharmacol 2023; 121:110530. [PMID: 37348231 DOI: 10.1016/j.intimp.2023.110530] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2023] [Revised: 06/01/2023] [Accepted: 06/15/2023] [Indexed: 06/24/2023]
Abstract
The C-X-C motif ligand 16, or CXCL16, is a chemokine that belongs to the ELR - CXC subfamily. Its function is to bind to the chemokine receptor CXCR6, which is a G protein-coupled receptor with 7 transmembrane domains. The CXCR6/CXCL16 axis has been linked to the development of numerous autoimmune diseases and is connected to clinical parameters that reflect disease severity, activity, and prognosis in conditions such as multiple sclerosis, autoimmune hepatitis, rheumatoid arthritis, Crohn's disease, and psoriasis. CXCL16 is expressed in various immune cells, such as dendritic cells, monocytes, macrophages, and B cells. During autoimmune diseases, CXCL16 can facilitate the adhesion of immune cells like monocytes, T cells, NKT cells, and others to endothelial cells and dendritic cells. Additionally, sCXCL16 can regulate the migration of CXCR6-expressing leukocytes, which includes CD8+ T cells, CD4+ T cells, NK cells, constant natural killer T cells, plasma cells, and monocytes. Further investigation is required to comprehend the intricate interactions between chemokines and the pathogenesis of autoimmune diseases. It remains to be seen whether the CXCR6/CXCL16 axis represents a new target for the treatment of these conditions.
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Affiliation(s)
- Nandi Bao
- Senior Department of Cardiology, The Sixth Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Bo Fu
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, Beijing, China; State Key Laboratory of Kidney Diseases, Chinese PLA General Hospital, Beijing, China
| | - Xiaoling Zhong
- Department of neurology, School of Medicine, South China University of Technology, Guangzhou, China; Department of neurology, The Sixth Medical Center of PLA General Hospital of Beijing, Beijing, China
| | - Shuangshuang Jia
- Department of neurology, The Sixth Medical Center of PLA General Hospital of Beijing, Beijing, China; Navy Clinical College, the Fifth School of Clinical Medicine, Anhui Medical University, Hefei, China
| | - Zhuangzhuang Ren
- Navy Clinical College, the Fifth School of Clinical Medicine, Anhui Medical University, Hefei, China
| | - Haoran Wang
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, Beijing, China; State Key Laboratory of Kidney Diseases, Chinese PLA General Hospital, Beijing, China
| | - Weihua Wang
- Department of Gastroenterology, The Second Medical Center, Chinese PLA General Hospital, Beijing, China; National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing, China
| | - Hui Shi
- Department of Gastroenterology, The Second Medical Center, Chinese PLA General Hospital, Beijing, China; National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing, China
| | - Jun Li
- Department of Gastroenterology, The Second Medical Center, Chinese PLA General Hospital, Beijing, China; National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing, China
| | - Fulin Ge
- Department of Gastroenterology, The Second Medical Center, Chinese PLA General Hospital, Beijing, China; National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing, China
| | - Qing Chang
- Department of Gastroenterology, The Second Medical Center, Chinese PLA General Hospital, Beijing, China; National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing, China
| | - Yuan Gong
- Department of Gastroenterology, The Second Medical Center, Chinese PLA General Hospital, Beijing, China; National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing, China
| | - Wenhui Liu
- Department of Gastroenterology, The Second Medical Center, Chinese PLA General Hospital, Beijing, China; National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing, China
| | - Feng Qiu
- Senior Department of Neurology, The First Medical Center of PLA General Hospital, Beijing, China.
| | - Shiping Xu
- Department of Gastroenterology, The Second Medical Center, Chinese PLA General Hospital, Beijing, China; National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing, China.
| | - Tingting Li
- State Key Laboratory of Kidney Diseases, Chinese PLA General Hospital, Beijing, China; Department of Gastroenterology, The Second Medical Center, Chinese PLA General Hospital, Beijing, China; National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing, China.
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Papanastasatou M, Verykokakis M. Innate-like T lymphocytes in chronic liver disease. Front Immunol 2023; 14:1114605. [PMID: 37006304 PMCID: PMC10050337 DOI: 10.3389/fimmu.2023.1114605] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Accepted: 02/28/2023] [Indexed: 03/17/2023] Open
Abstract
In addition to its metabolic activities, it is now clear that the liver hosts a number of diverse immune cell types that control tissue homeostasis. Foremost among these are innate-like T lymphocytes, including natural killer T (NKT) and mucosal-associated innate T (MAIT) cells, which are a population of specialized T cells with innate characteristics that express semi-invariant T cell receptors with non-peptide antigen specificity. As primary liver residents, innate-like T cells have been associated with immune tolerance in the liver, but also with a number of hepatic diseases. Here, we focus on the biology of NKT and MAIT cells and how they operate during the course of chronic inflammatory diseases that eventually lead to hepatocellular carcinoma.
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Jaén M, Martín-Regalado Á, Bartolomé RA, Robles J, Casal JI. Interleukin 13 receptor alpha 2 (IL13Rα2): Expression, signaling pathways and therapeutic applications in cancer. Biochim Biophys Acta Rev Cancer 2022; 1877:188802. [PMID: 36152905 DOI: 10.1016/j.bbcan.2022.188802] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Revised: 09/05/2022] [Accepted: 09/11/2022] [Indexed: 10/14/2022]
Abstract
Interleukin 13 receptor alpha 2 (IL13Rα2) is increasingly recognized as a relevant player in cancer invasion and metastasis. Despite being initially considered a decoy receptor for dampening the levels of interleukin 13 (IL-13) in diverse inflammatory conditions, accumulating evidences in the last decades indicate the capacity of IL13Rα2 for mediating IL-13 signaling in cancer cells. The biological reasons behind the expression of this receptor with such extremely high affinity for IL-13 in cancer cells remain unclear. Elevated expression of IL13Rα2 is commonly associated with invasion, late stage and cancer metastasis that results in poor prognosis for glioblastoma, colorectal or breast cancer, among others. The discovery of new mediators and effectors of IL13Rα2 signaling has been critical for deciphering its underlying molecular mechanisms in cancer progression. Still, many questions about the effects of inflammation, the cancer type and the tumor degree in the expression of IL13Rα2 remain largely uncharacterized. Here, we review and discuss the current status of the IL13Rα2 biology in cancer, with particular emphasis in the role of inflammation-driven expression and the regulation of different signaling pathways. As IL13Rα2 implications in cancer continue to grow exponentially, we highlight new targeted therapies recently developed for glioblastoma, colorectal cancer and other IL13Rα2-positive tumors.
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Affiliation(s)
- Marta Jaén
- Department of Molecular Biomedicine, Centro de Investigaciones Biológicas Margarita Salas, CSIC, Ramiro de Maeztu 9, 28040 Madrid, Spain
| | - Ángela Martín-Regalado
- Department of Molecular Biomedicine, Centro de Investigaciones Biológicas Margarita Salas, CSIC, Ramiro de Maeztu 9, 28040 Madrid, Spain
| | - Rubén A Bartolomé
- Department of Molecular Biomedicine, Centro de Investigaciones Biológicas Margarita Salas, CSIC, Ramiro de Maeztu 9, 28040 Madrid, Spain
| | - Javier Robles
- Department of Molecular Biomedicine, Centro de Investigaciones Biológicas Margarita Salas, CSIC, Ramiro de Maeztu 9, 28040 Madrid, Spain; Protein Alternatives SL, Tres Cantos, Madrid, Spain
| | - J Ignacio Casal
- Department of Molecular Biomedicine, Centro de Investigaciones Biológicas Margarita Salas, CSIC, Ramiro de Maeztu 9, 28040 Madrid, Spain.
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Senff T, Menne C, Cosmovici C, Lewis-Ximenez LL, Aneja J, Broering R, Kim AY, Westendorf AM, Dittmer U, Scherbaum N, Lauer GM, Timm J. Peripheral blood iNKT cell activation correlates with liver damage during acute hepatitis C. JCI Insight 2021; 7:155432. [PMID: 34905514 PMCID: PMC8855829 DOI: 10.1172/jci.insight.155432] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Accepted: 12/08/2021] [Indexed: 11/17/2022] Open
Abstract
Invariant NK T (iNKT) cells are implicated in viral clearance; however, their role in hepatitis C virus (HCV) infection remains controversial. Here, iNKT cells were studied during different stages of HCV infection. iNKT cells from patients with acute HCV infection and people who inject drugs (PWID) with chronic or spontaneously resolved HCV infection were characterized by flow cytometry. In a longitudinal analysis during acute HCV infection, frequencies of activated CD38+ iNKT cells reproducibly declined in spontaneously resolving patients, whereas they were persistently elevated in patients progressing to chronic infection. During the first year of infection, the frequency of activated CD38+ or CD69+ iNKT cells strongly correlated with alanine transaminase levels with particularly pronounced correlations in spontaneously resolving patients. Increased frequencies of activated iNKT cells in chronic HCV infection were confirmed in cross-sectional analyses of PWID with chronic or spontaneously resolved HCV infection; however, no apparent functional differences were observed with various stimulation protocols. Our data suggest that iNKT cells are activated during acute hepatitis C and that activation is sustained in chronic infection. The correlation between the frequency of activated iNKT cells and alanine transaminase may point toward a role of iNKT cells in liver damage.
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Affiliation(s)
- Tina Senff
- Institute of Virology, University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, Germany
| | - Christopher Menne
- Institute of Virology, University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, Germany
| | - Christine Cosmovici
- Institute of Virology, University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, Germany
| | | | - Jasneet Aneja
- Gastrointestinal Unit, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America
| | - Ruth Broering
- Department of Gastroenterology and Hepatology, University Hospital, University Duisburg-Essen, Essen, Germany
| | - Arthur Y Kim
- Department of Medicine, Massachusetts General Hospital, Boston, United States of America
| | - Astrid M Westendorf
- Institute of Medical Microbiology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Ulf Dittmer
- Institute of Virology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Norbert Scherbaum
- Department for Addiction Medicine and Addictive Behavior, LVR-Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Georg M Lauer
- Gastrointestinal Unit, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America
| | - Jörg Timm
- Institute of Virology, University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, Germany
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Romanelli RG, Vitiello G, Gitto S, Giudizi MG, Biagiotti R, Carraresi A, Vizzutti F, Laffi G, Almerigogna F. Characterization of lymphocyte subsets in ascitic fluid and peripheral blood of decompensated cirrhotic patients with chronic hepatitis C and alcoholic liver disease: A pivotal study. Int J Immunopathol Pharmacol 2021; 34:2058738420929587. [PMID: 32524881 PMCID: PMC7290250 DOI: 10.1177/2058738420929587] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
Hepatitis C virus and alcoholic liver disease are major causes of chronic liver diseases worldwide. Little is known about differences between chronic hepatitis C and alcoholic liver disease in terms of lymphocytes’ sub-population. Aim of the present study was to compare the sub-populations of lymphocytes in both ascitic compartment and peripheral blood in patients with decompensated liver cirrhosis due to chronic hepatitis C and alcoholic liver disease. Patients with decompensated liver cirrhosis due to hepatitis C virus or alcoholic liver disease evaluated from April 2014 to October 2016 were enrolled. Whole blood and ascitic fluid samples were stained with monoclonal antibodies specific for human TCRɑβ, TCRɣδ, CD3, CD4, CD8, CD19, CCR6, CD16, CD56, CD25, HLA-DR, Vɑ24. Sixteen patients with decompensated liver cirrhosis were recruited (9 with hepatitis C virus and 7 with alcoholic liver disease). In ascitic fluid, the percentage of both CD3+CD56− and CD3+CD56+iNKT cells resulted higher in hepatitis C virus patients than in alcoholic liver disease patients (1.82 ± 0.35% vs 0.70 ± 0.42% (p < 0.001) and 1.42 ± 0.35% vs 0.50 ± 0.30% (p < 0.001), respectively). Conversely, in peripheral blood samples, both CD3+CD56− and CD3+CD56+iNKT cells resulted significantly higher in alcoholic liver disease than in hepatitis C virus patients (4.70 ± 2.69% vs 1.50 ± 1.21% (p < 0.01) and 3.10 ± 1.76% vs 1.00 ± 0.70% (p < 0.01), respectively). Both elevation of iNKT cells in ascitic fluid and reduction in peripheral blood registered in hepatitis C virus but not in alcoholic liver disease patients might be considered indirect signals of tissutal translocation. In conclusion, we described relevant differences between the two groups. Alcoholic liver disease patients displayed lower number of CD3+CD4+ cells and a higher percentage of CD3−CD16+, Vα24+CD3+CD56− and Vα24+CD3+CD56+iNKT cells in ascitic fluid than hepatitis C virus positive subjects. Further studies might analyze the role of immune cells in the vulnerability toward infections and detect potential targets for new treatments especially for alcoholic liver disease patients.
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Affiliation(s)
- Roberto Giulio Romanelli
- Internal Medicine and Liver Unit, Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Gianfranco Vitiello
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Stefano Gitto
- Internal Medicine and Liver Unit, Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Maria Grazia Giudizi
- Immunoallergology Unit, Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Roberta Biagiotti
- Immunoallergology Unit, Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Alessia Carraresi
- Immunoallergology Unit, Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Francesco Vizzutti
- Internal Medicine and Liver Unit, Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Giacomo Laffi
- Internal Medicine and Liver Unit, Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Fabio Almerigogna
- Immunoallergology Unit, Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
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11
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Sepulveda-Crespo D, Resino S, Martinez I. Strategies Targeting the Innate Immune Response for the Treatment of Hepatitis C Virus-Associated Liver Fibrosis. Drugs 2021; 81:419-443. [PMID: 33400242 DOI: 10.1007/s40265-020-01458-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Direct-acting antivirals eliminate hepatitis C virus (HCV) in more than 95% of treated individuals and may abolish liver injury, arrest fibrogenesis, and reverse fibrosis and cirrhosis. However, liver regeneration is usually a slow process that is less effective in the late stages of fibrosis. What is more, fibrogenesis may prevail in patients with advanced cirrhosis, where it can progress to liver failure and hepatocellular carcinoma. Therefore, the development of antifibrotic drugs that halt and reverse fibrosis progression is urgently needed. Fibrosis occurs due to the repair process of damaged hepatic tissue, which eventually leads to scarring. The innate immune response against HCV is essential in the initiation and progression of liver fibrosis. HCV-infected hepatocytes and liver macrophages secrete proinflammatory cytokines and chemokines that promote the activation and differentiation of hepatic stellate cells (HSCs) to myofibroblasts that produce extracellular matrix (ECM) components. Prolonged ECM production by myofibroblasts due to chronic inflammation is essential to the development of fibrosis. While no antifibrotic therapy is approved to date, several drugs are being tested in phase 2 and phase 3 trials with promising results. This review discusses current state-of-the-art knowledge on treatments targeting the innate immune system to revert chronic hepatitis C-associated liver fibrosis. Agents that cause liver damage may vary (alcohol, virus infection, etc.), but fibrosis progression shows common patterns among them, including chronic inflammation and immune dysregulation, hepatocyte injury, HSC activation, and excessive ECM deposition. Therefore, mechanisms underlying these processes are promising targets for general antifibrotic therapies.
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Affiliation(s)
- Daniel Sepulveda-Crespo
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III (Campus Majadahonda), Carretera Majadahonda-Pozuelo, Km 2.2, 28220, Majadahonda, Madrid, Spain
| | - Salvador Resino
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III (Campus Majadahonda), Carretera Majadahonda-Pozuelo, Km 2.2, 28220, Majadahonda, Madrid, Spain.
| | - Isidoro Martinez
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III (Campus Majadahonda), Carretera Majadahonda-Pozuelo, Km 2.2, 28220, Majadahonda, Madrid, Spain.
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12
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Plasma Inflammatory Biomarkers Associated with Advanced Liver Fibrosis in HIV-HCV-Coinfected Individuals. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2020; 17:ijerph17249474. [PMID: 33348839 PMCID: PMC7766690 DOI: 10.3390/ijerph17249474] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Revised: 11/25/2020] [Accepted: 12/08/2020] [Indexed: 11/16/2022]
Abstract
BACKGROUND HIV and HCV coinfection leads to accelerated liver fibrosis, in which microbial translocation and systemic inflammation might play important roles. OBJECTIVE This study aimed to provide an extensive profile of the plasma microbial translocation and inflammation biomarkers associated with advanced liver fibrosis among HIV-HCV-coinfected patients. METHODS This cross-sectional study recruited 343 HIV-HCV-coinfected patients on combination antiretroviral therapy (cART) from a rural prefecture of Yunnan province in Southwest China. The plasma concentrations of sCD14 and 27 cytokines and chemokines were assayed and compared against advanced or mild levels of liver fibrosis. RESULTS Of the 343 HIV-HCV-coinfected patients, 188 (54.8%) had severe or advanced liver fibrosis (FIB-4 > 3.25). The patients with advanced liver fibrosis (FIB-4 > 3.25 vs. FIB-4 ≤ 3.25) had higher plasma levels of interleukin (IL)-1β, IL-6, IL-7, IL-9, IL-12, IL-15, IL-17, granulocyte macrophage colony stimulating factor (GM-CSF), Interferon-γ (IFN-γ), tumor necrosis factor (TNF-α), IL-4, IL-10, IL-13, fibroblast growth factor 2 (FGF-basic), and Monocyte chemoattractant protein-1 (MCP-1). Multivariable logistic regression models showed that advanced liver fibrosis was associated with an increased plasma level of IL-1β, IL-6, IL-7, IL-12, IL-17, GM-CSF, IFN-γ, IL-4, IL-10, MCP-1, Eotaxin, and FGF-basic, with FGF-basic continuing to be positively and significantly associated with advanced liver fibrosis, after Bonferroni correction for multiple comparisons (adjusted odds ratio (aOR) = 1.92; 95%CI: 1.32-2.81; p = 0.001). Plasma sCD14 was also significantly associated with advanced liver fibrosis (aOR = 1.13; 95%CI: 1.01-1.30; p = 0.049). CONCLUSIONS HIV-HCV-coinfected patients are living with a high prevalence of advanced liver fibrosis which coexists with a mixture of elevated plasma inflammation and microbial translocation biomarkers. The significant associations of advanced liver fibrosis with FGF-basic and sCD14 may reveal pathogenic mechanisms and potential clinical intervention targets for liver fibrosis in HCV-HIV coinfection.
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13
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Wang W, Huang X, Fan X, Yan J, Luan J. Progress in evaluating the status of hepatitis C infection based on the functional changes of hepatic stellate cells (Review). Mol Med Rep 2020; 22:4116-4124. [PMID: 33000255 DOI: 10.3892/mmr.2020.11516] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Accepted: 08/18/2020] [Indexed: 11/06/2022] Open
Abstract
Hepatitis C virus (HCV) infection is a global public health problem. Cirrhosis and hepatocellular carcinoma are the main causes of death in patients with chronic hepatitis C (CHC) infection. Liver fibrosis is an important cause of cirrhosis and end‑stage liver disease after CHC infection. Along with the course of infection, liver fibrosis exhibits a progressive exacerbation. Hepatic stellate cells (HSCs) are involved in both physiological and pathological processes of the liver. During the chronic liver injury process, the activated HSCs transform into myofibroblasts, which are important cells in the development of liver fibrosis. At present, HCV infection still lacks specific markers for the accurate detection of the disease condition and progression. Therefore, the present review focused on HSCs, which are closely related to HCV‑infected liver fibrosis, and analyzed the changes in the HSCs, including their surface‑specific markers, cytokine production, activation, cell function and morphological structure. The present review aimed to propose novel diagnostic markers, at both the cellular and molecular level, which would be of great significance for the timely diagnosis of the disease. According to this aim, the characteristic changes of HSCs during HCV infection were reviewed in the present article.
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Affiliation(s)
- Wei Wang
- Department of Blood Transfusion Medicine, School of Medicine, Jinling Hospital, Nanjing University, Nanjing, Jiangsu 210002, P.R. China
| | - Xuelian Huang
- Department of Blood Transfusion Medicine, School of Medicine, Jinling Hospital, Nanjing University, Nanjing, Jiangsu 210002, P.R. China
| | - Xuzhou Fan
- Department of Blood Transfusion Medicine, School of Medicine, Jinling Hospital, Nanjing University, Nanjing, Jiangsu 210002, P.R. China
| | - Jingmei Yan
- Department of Blood Transfusion Medicine, School of Medicine, Jinling Hospital, Nanjing University, Nanjing, Jiangsu 210002, P.R. China
| | - Jianfeng Luan
- Department of Blood Transfusion Medicine, School of Medicine, Jinling Hospital, Nanjing University, Nanjing, Jiangsu 210002, P.R. China
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14
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Chronic Viral Liver Diseases: Approaching the Liver Using T Cell Receptor-Mediated Gene Technologies. Cells 2020; 9:cells9061471. [PMID: 32560123 PMCID: PMC7349849 DOI: 10.3390/cells9061471] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Revised: 06/04/2020] [Accepted: 06/09/2020] [Indexed: 12/11/2022] Open
Abstract
Chronic infection with viral hepatitis is a major risk factor for liver injury and hepatocellular carcinoma (HCC). One major contributing factor to the chronicity is the dysfunction of virus-specific T cell immunity. T cells engineered to express virus-specific T cell receptors (TCRs) may be a therapeutic option to improve host antiviral responses and have demonstrated clinical success against virus-associated tumours. This review aims to give an overview of TCRs identified from viral hepatitis research and discuss how translational lessons learned from cancer immunotherapy can be applied to the field. TCR isolation pipelines, liver homing signals, cell type options, as well as safety considerations will be discussed herein.
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15
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Cao Y, Ji C, Lu L. Mesenchymal stem cell therapy for liver fibrosis/cirrhosis. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:562. [PMID: 32775363 PMCID: PMC7347778 DOI: 10.21037/atm.2020.02.119] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Liver fibrosis represents a common outcome of most chronic liver diseases. Advanced fibrosis leads to cirrhosis for which no effective treatment is available except liver transplantation. Because of the limitations of liver transplantation, alternative therapeutic strategies are an urgent need to find. Recently, mesenchymal stem cells (MSCs) based therapy has been suggested as an attractive therapeutic option for liver fibrosis and cirrhosis, based on the promising results from preclinical and clinical studies. Although the precise mechanisms of MSC transplantation are still not fully understood, accumulating evidence has indicated that MSCs eliminate the progression of fibrosis due to their immune-modulatory properties. In this review, we summarise the properties of MSCs and their clinical application in the treatment of liver fibrosis and cirrhosis. We also discuss the mechanisms involved in MSC-dependent regulation of immune microenvironment in the context of liver fibrosis and cirrhosis.
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Affiliation(s)
- Yan Cao
- Nanjing Maternity and Child Health Care Institute, Women's Hospital of Nanjing Medical University (Nanjing Maternity and Child Health Care Hospital), Nanjing 210004, China
| | - Chenbo Ji
- Nanjing Maternity and Child Health Care Institute, Women's Hospital of Nanjing Medical University (Nanjing Maternity and Child Health Care Hospital), Nanjing 210004, China
| | - Ling Lu
- Liver Transplantation Center, First Affiliated Hospital, Nanjing Medical University, Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing 210029, China.,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing 210029, China
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16
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17
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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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18
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Townsend EC, Zhang GY, Ali R, Firke M, Moon MS, Han MAT, Fram B, Glenn JS, Kleiner DE, Koh C, Heller T. The balance of type 1 and type 2 immune responses in the contexts of hepatitis B infection and hepatitis D infection. J Gastroenterol Hepatol 2019; 34:764-775. [PMID: 30695096 PMCID: PMC8237314 DOI: 10.1111/jgh.14617] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2018] [Revised: 01/10/2019] [Accepted: 01/22/2019] [Indexed: 12/15/2022]
Abstract
BACKGROUND AND AIM Hepatitis delta virus (HDV) infection is the most rapidly progressive chronic viral hepatitis. Little is understood about the immune responses to HDV. This study aims to characterize the systemic immune environments of hepatitis B virus (HBV) and HDV patients at various disease stages. METHODS A total of 129 subjects were evaluated: 53 HBV, 43 HDV, and 33 healthy controls. HBV and HDV subjects were categorized by aspartate aminotransferase to platelet ratio index (APRI) into mild (APRI < 0.5), moderate, and severe (APRI > 1.0). Serum cytokines and immune markers were assessed at a single treatment-naïve time-point. RESULTS Type 1 cytokines are elevated in both HBV and HDV. Both groups show higher tumor necrosis factor-α (TNF-α), interleukin (IL)-12p40, and C-X-C motif chemokine ligand 9 when compared with controls (all P < 0.05). However, only HBV group displayed elevated γ-interferon compared with controls. Type 2 cytokines are elevated in HBV. HBV group shows higher IL-4, IL-13, and C-C motif chemokine ligand (CCL) 26 compared with healthy controls and HDV. Chemokines CCL2 and CCL13 are lower in HDV. When assessing ratios, HDV displays higher γ-interferon/IL-4, TNF-α/IL-4, and TNF-α/IL-13 ratios than HBV and controls. CONCLUSION Hepatitis B virus and HDV subjects show similarly elevated type 1 cytokines. HDV subjects display relatively lower type 2 cytokines. These differences in the systemic immune environments, particularly the predominance of type 1 responses, may contribute to the comparatively rapid progression of HDV disease. Characterization of the imbalance in type 1 and type 2 immunity unique HDV has the potential to provide immunological insights for designing therapeutic targets in HDV-associated disease progression.
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Affiliation(s)
- Elizabeth C Townsend
- Liver Diseases Branch, National Institute of Diabetes, Digestive, and Kidney Diseases, Bethesda, Maryland
| | - Grace Y Zhang
- Liver Diseases Branch, National Institute of Diabetes, Digestive, and Kidney Diseases, Bethesda, Maryland
| | - Rabab Ali
- Liver Diseases Branch, National Institute of Diabetes, Digestive, and Kidney Diseases, Bethesda, Maryland
| | - Marian Firke
- Liver Diseases Branch, National Institute of Diabetes, Digestive, and Kidney Diseases, Bethesda, Maryland
| | - Mi Sun Moon
- Liver Diseases Branch, National Institute of Diabetes, Digestive, and Kidney Diseases, Bethesda, Maryland
| | - Ma Ai Thanda Han
- Liver Diseases Branch, National Institute of Diabetes, Digestive, and Kidney Diseases, Bethesda, Maryland
| | - Benjamin Fram
- Department of Medicine, Stanford University, Stanford
| | - Jeffrey S Glenn
- Department of Medicine, Stanford University, Stanford,Department of Microbiology and Immunology, Stanford University, Stanford,Department of Medicine, Veterans Administration Medical Center, Palo Alto, California, USA
| | - David E Kleiner
- Laboratory of Pathology, National Cancer Institute, Bethesda, Maryland
| | - Christopher Koh
- Liver Diseases Branch, National Institute of Diabetes, Digestive, and Kidney Diseases, Bethesda, Maryland
| | - Theo Heller
- Liver Diseases Branch, National Institute of Diabetes, Digestive, and Kidney Diseases, Bethesda, Maryland
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19
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Cortesi F, Delfanti G, Casorati G, Dellabona P. The Pathophysiological Relevance of the iNKT Cell/Mononuclear Phagocyte Crosstalk in Tissues. Front Immunol 2018; 9:2375. [PMID: 30369933 PMCID: PMC6194905 DOI: 10.3389/fimmu.2018.02375] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2018] [Accepted: 09/24/2018] [Indexed: 12/14/2022] Open
Abstract
CD1d-restricted Natural Killer T (NKT) cells are regarded as sentinels of tissue integrity by sensing local cell stress and damage. This occurs via recognition of CD1d-restricted lipid antigens, generated by stress-related metabolic changes, and stimulation by inflammatory cytokines, such as IL-12 and IL-18. Increasing evidence suggest that this occurs mainly upon NKT cell interaction with CD1d-expressing cells of the Mononuclear Phagocytic System, i.e., monocytes, macrophages and DCs, which patrol parenchymatous organs and mucosae to maintain tissue homeostasis and immune surveillance. In this review, we discuss critical examples of this crosstalk, presenting the known underlying mechanisms and their effects on both cell types and the environment, and suggest that the interaction with CD1d-expressing mononuclear phagocytes in tissues is the fundamental job of NKT cells.
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Affiliation(s)
- Filippo Cortesi
- Experimental Immunology Unit, Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Gloria Delfanti
- Experimental Immunology Unit, Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy.,Università Vita-Salute San Raffaele, Milan, Italy
| | - Giulia Casorati
- Experimental Immunology Unit, Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Paolo Dellabona
- Experimental Immunology Unit, Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy
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20
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Tan X, Ding Y, Zhu P, Dou R, Liang Z, Yang D, Huang Z, Wang W, Wu X, Weng X. Elevated Hepatic CD1d Levels Coincide with Invariant NKT Cell Defects in Chronic Hepatitis B Virus Infection. THE JOURNAL OF IMMUNOLOGY 2018; 200:3530-3538. [DOI: 10.4049/jimmunol.1701801] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/02/2018] [Accepted: 03/15/2018] [Indexed: 12/23/2022]
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22
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Cannizzo ES, Tincati C, Binda F, Ronzi P, Cazzaniga FA, Antinori S, d'Arminio Monforte A, Marchetti G, Milazzo L. Unconventional T cells in chronic hepatitis B patients on long-term suppressive therapy with tenofovir followed by a Peg-IFN add-on strategy: A randomized study. J Viral Hepat 2018; 25:381-390. [PMID: 29091327 DOI: 10.1111/jvh.12820] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2017] [Accepted: 09/19/2017] [Indexed: 12/21/2022]
Abstract
HBV eradication in chronic hepatitis B (CHB) subjects is rarely achieved with either nucleos(t)ide analogues (NA) or pegylated interferon (Peg-IFN), which both have a limited effect in restoring immune responses. Thirty CHB subjects on long-term treatment with tenofovir (TDF) and HBV suppression were enrolled and randomized 1:2 to either receive Peg-IFN-α-2a add-on therapy or continue TDF alone. We studied γδ T and iNKT frequency and function (by flow cytometry) at baseline, at 12 weeks and 12 weeks after the end of treatment. A higher reduction in qHBsAg occurred in the add-on group compared with the NA group at W12 (P = .016) and at W24 (P = .012). A decline of qHBsAg ≥0.5 log10 at week 24 occurred in 4 of 10 patients in the add-on arm and 1 of 20 in the NA arm, respectively (P = .03). HBsAg loss was seen in 20% of subjects in the add-on group and in none of the NA group. Compared to HBV negative, CHB on TDF showed lower frequency of iNKT (P = .03) and γδ T cells (P = .03) as well as fewer γδ T cells expressing Vδ2 T-cell receptors (P = .005). No changes in unconventional T-cell frequency and function were shown in both add-on and NA patients nor were differences detected between the two treatment groups. We report persistent impairment of unconventional T cells in CHB. Despite a greater qHBsAg decline of add-on patients, our data failed to detect any effect of Peg-IFN treatment on unconventional T cells.
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Affiliation(s)
- E S Cannizzo
- Department of Health Sciences, Clinic of Infectious Diseases, ASST Santi Paolo e Carlo, University of Milan, Milan, Italy
| | - C Tincati
- Department of Health Sciences, Clinic of Infectious Diseases, ASST Santi Paolo e Carlo, University of Milan, Milan, Italy
| | - F Binda
- Department of Clinical and Biomedical Sciences Luigi Sacco, III Division of Infectious Diseases, University of Milan, Milan, Italy
| | - P Ronzi
- Department of Clinical and Biomedical Sciences Luigi Sacco, III Division of Infectious Diseases, University of Milan, Milan, Italy
| | - F A Cazzaniga
- Department of Health Sciences, Clinic of Infectious Diseases, ASST Santi Paolo e Carlo, University of Milan, Milan, Italy
| | - S Antinori
- Department of Clinical and Biomedical Sciences Luigi Sacco, III Division of Infectious Diseases, University of Milan, Milan, Italy
| | - A d'Arminio Monforte
- Department of Health Sciences, Clinic of Infectious Diseases, ASST Santi Paolo e Carlo, University of Milan, Milan, Italy
| | - G Marchetti
- Department of Health Sciences, Clinic of Infectious Diseases, ASST Santi Paolo e Carlo, University of Milan, Milan, Italy
| | - L Milazzo
- Department of Clinical and Biomedical Sciences Luigi Sacco, III Division of Infectious Diseases, University of Milan, Milan, Italy
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23
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Schönrich G, Raftery MJ. CD1-Restricted T Cells During Persistent Virus Infections: "Sympathy for the Devil". Front Immunol 2018; 9:545. [PMID: 29616036 PMCID: PMC5868415 DOI: 10.3389/fimmu.2018.00545] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2018] [Accepted: 03/02/2018] [Indexed: 12/12/2022] Open
Abstract
Some of the clinically most important viruses persist in the human host after acute infection. In this situation, the host immune system and the viral pathogen attempt to establish an equilibrium. At best, overt disease is avoided. This attempt may fail, however, resulting in eventual loss of viral control or inadequate immune regulation. Consequently, direct virus-induced tissue damage or immunopathology may occur. The cluster of differentiation 1 (CD1) family of non-classical major histocompatibility complex class I molecules are known to present hydrophobic, primarily lipid antigens. There is ample evidence that both CD1-dependent and CD1-independent mechanisms activate CD1-restricted T cells during persistent virus infections. Sophisticated viral mechanisms subvert these immune responses and help the pathogens to avoid clearance from the host organism. CD1-restricted T cells are not only crucial for the antiviral host defense but may also contribute to tissue damage. This review highlights the two edged role of CD1-restricted T cells in persistent virus infections and summarizes the viral immune evasion mechanisms that target these fascinating immune cells.
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Affiliation(s)
- Günther Schönrich
- Berlin Institute of Health, Institute of Virology, Charité-Universitätsmedizin Berlin, Humboldt-Universität zu Berlin, Berlin, Germany
| | - Martin J Raftery
- Berlin Institute of Health, Institute of Virology, Charité-Universitätsmedizin Berlin, Humboldt-Universität zu Berlin, Berlin, Germany
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24
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Keller CW, Freigang S, Lünemann JD. Reciprocal Crosstalk between Dendritic Cells and Natural Killer T Cells: Mechanisms and Therapeutic Potential. Front Immunol 2017; 8:570. [PMID: 28596767 PMCID: PMC5442181 DOI: 10.3389/fimmu.2017.00570] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2017] [Accepted: 04/28/2017] [Indexed: 12/23/2022] Open
Abstract
Natural killer T cells carrying a highly conserved, semi-invariant T cell receptor (TCR) [invariant natural killer T (iNKT) cells] are a subset of unconventional T lymphocytes that recognize glycolipids presented by CD1d molecules. Although CD1d is expressed on a variety of hematopoietic and non-hematopoietic cells, dendritic cells (DCs) are key presenters of glycolipid antigen in vivo. When stimulated through their TCR, iNKT cells rapidly secrete copious amounts of cytokines and induce maturation of DCs, thereby facilitating coordinated stimulation of innate and adaptive immune responses. The bidirectional crosstalk between DCs and iNKT cells determines the functional outcome of iNKT cell-targeted responses and iNKT cell agonists are used and currently being evaluated as adjuvants to enhance the efficacy of antitumor immunotherapy. This review illustrates mechanistic underpinnings of reciprocal DCs and iNKT cell interactions and discusses how those can be harnessed for cancer therapy.
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Affiliation(s)
- Christian W Keller
- Institute of Experimental Immunology, Laboratory of Neuroinflammation, University of Zurich, Zurich, Switzerland
| | - Stefan Freigang
- Institute of Pathology, Laboratory of Immunopathology, University of Bern, Bern, Switzerland
| | - Jan D Lünemann
- Institute of Experimental Immunology, Laboratory of Neuroinflammation, University of Zurich, Zurich, Switzerland.,Department of Neurology, University Hospital Zurich, Zurich, Switzerland
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25
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Catarinella M, Monestiroli A, Escobar G, Fiocchi A, Tran NL, Aiolfi R, Marra P, Esposito A, Cipriani F, Aldrighetti L, Iannacone M, Naldini L, Guidotti LG, Sitia G. IFNα gene/cell therapy curbs colorectal cancer colonization of the liver by acting on the hepatic microenvironment. EMBO Mol Med 2016; 8:155-70. [PMID: 26769348 PMCID: PMC4734840 DOI: 10.15252/emmm.201505395] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Colorectal cancer (CRC) metastatic dissemination to the liver is one of the most life‐threatening malignancies in humans and represents the leading cause of CRC‐related mortality. Herein, we adopted a gene transfer strategy into mouse hematopoietic stem/progenitor cells to generate immune‐competent mice in which TEMs—a subset of Tie2+ monocytes/macrophages found at peritumoral sites—express interferon‐alpha (IFNα), a pleiotropic cytokine with anti‐tumor effects. Utilizing this strategy in mouse models of CRC liver metastasis, we show that TEMs accumulate in the proximity of hepatic metastatic areas and that TEM‐mediated delivery of IFNα inhibits tumor growth when administered prior to metastasis challenge as well as on established hepatic lesions, improving overall survival. Further analyses unveiled that local delivery of IFNα does not inhibit homing but limits the early phases of hepatic CRC cell expansion by acting on the radio‐resistant hepatic microenvironment. TEM‐mediated IFNα expression was not associated with systemic side effects, hematopoietic toxicity, or inability to respond to a virus challenge. Along with the notion that TEMs were detected in the proximity of CRC metastases in human livers, these results raise the possibility to employ similar gene/cell therapies as tumor site‐specific drug‐delivery strategies in patients with CRC.
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Affiliation(s)
- Mario Catarinella
- Division of Immunology, Transplantation and Infectious Diseases IRCCS San Raffaele Scientific Institute, Milan, Italy Vita-Salute San Raffaele University, Milan, Italy
| | - Andrea Monestiroli
- Division of Immunology, Transplantation and Infectious Diseases IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Giulia Escobar
- Vita-Salute San Raffaele University, Milan, Italy Angiogenesis and Tumor Targeting Research Unit and San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Amleto Fiocchi
- Division of Immunology, Transplantation and Infectious Diseases IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Ngoc Lan Tran
- Division of Immunology, Transplantation and Infectious Diseases IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Roberto Aiolfi
- Division of Immunology, Transplantation and Infectious Diseases IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Paolo Marra
- Vita-Salute San Raffaele University, Milan, Italy Department of Radiology, IRCCS San Raffaele Scientific Institute, Milan, Italy Experimental Imaging Center, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Antonio Esposito
- Vita-Salute San Raffaele University, Milan, Italy Department of Radiology, IRCCS San Raffaele Scientific Institute, Milan, Italy Experimental Imaging Center, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Federica Cipriani
- Hepatopancreatobiliary Surgery Unit, IRCCS San Raffaele Hospital, Milan, Italy
| | - Luca Aldrighetti
- Hepatopancreatobiliary Surgery Unit, IRCCS San Raffaele Hospital, Milan, Italy
| | - Matteo Iannacone
- Division of Immunology, Transplantation and Infectious Diseases IRCCS San Raffaele Scientific Institute, Milan, Italy Vita-Salute San Raffaele University, Milan, Italy Experimental Imaging Center, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Luigi Naldini
- Vita-Salute San Raffaele University, Milan, Italy Angiogenesis and Tumor Targeting Research Unit and San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Luca G Guidotti
- Division of Immunology, Transplantation and Infectious Diseases IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Giovanni Sitia
- Division of Immunology, Transplantation and Infectious Diseases IRCCS San Raffaele Scientific Institute, Milan, Italy
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A New Mouse Model That Spontaneously Develops Chronic Liver Inflammation and Fibrosis. PLoS One 2016; 11:e0159850. [PMID: 27441847 PMCID: PMC4956255 DOI: 10.1371/journal.pone.0159850] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2016] [Accepted: 07/09/2016] [Indexed: 12/21/2022] Open
Abstract
Here we characterize a new animal model that spontaneously develops chronic inflammation and fibrosis in multiple organs, the non-obese diabetic inflammation and fibrosis (N-IF) mouse. In the liver, the N-IF mouse displays inflammation and fibrosis particularly evident around portal tracts and central veins and accompanied with evidence of abnormal intrahepatic bile ducts. The extensive cellular infiltration consists mainly of macrophages, granulocytes, particularly eosinophils, and mast cells. This inflammatory syndrome is mediated by a transgenic population of natural killer T cells (NKT) induced in an immunodeficient NOD genetic background. The disease is transferrable to immunodeficient recipients, while polyclonal T cells from unaffected syngeneic donors can inhibit the disease phenotype. Because of the fibrotic component, early on-set, spontaneous nature and reproducibility, this novel mouse model provides a unique tool to gain further insight into the underlying mechanisms mediating transformation of chronic inflammation into fibrosis and to evaluate intervention protocols for treating conditions of fibrotic disorders.
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27
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Zou ZQ, Wang L, Wang K, Yu JG. Innate immune targets of hepatitis B virus infection. World J Hepatol 2016; 8:716-725. [PMID: 27330680 PMCID: PMC4911505 DOI: 10.4254/wjh.v8.i17.716] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2016] [Revised: 05/19/2016] [Accepted: 06/01/2016] [Indexed: 02/06/2023] Open
Abstract
Approximately 400 million people are chronically infected with hepatitis B virus (HBV) globally despite the widespread immunization of HBV vaccine and the development of antiviral therapies. The immunopathogenesis of HBV infection is initiated and driven by complexed interactions between the host immune system and the virus. Host immune responses to viral particles and proteins are regarded as the main determinants of viral clearance or persistent infection and hepatocyte injury. Innate immune system is the first defending line of host preventing from virus invasion. It is acknowledged that HBV has developed active tactics to escape innate immune recognition or actively interfere with innate immune signaling pathways and induce immunosuppression, which favor their replication. HBV reduces the expression of pattern-recognition receptors in the innate immune cells in humans. Also, HBV may interrupt different parts of antiviral signaling pathways, leading to the reduced production of antiviral cytokines such as interferons that contribute to HBV immunopathogenesis. A full comprehension of the mechanisms as to how HBV inactivates various elements of the innate immune response to initiate and maintain a persistent infection can be helpful in designing new immunotherapeutic methods for preventing and eradicating the virus. In this review, we aimed to summarize different branches the innate immune targeted by HBV infection. The review paper provides evidence that multiple components of immune responses should be activated in combination with antiviral therapy to disrupt the tolerance to HBV for eliminating HBV infection.
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Affiliation(s)
- Zhi-Qiang Zou
- Zhi-Qiang Zou, Li Wang, Ji-Guang Yu, Infectious Disease Hospital of Yantai, Yantai 264001, Shandong Province, China
| | - Li Wang
- Zhi-Qiang Zou, Li Wang, Ji-Guang Yu, Infectious Disease Hospital of Yantai, Yantai 264001, Shandong Province, China
| | - Kai Wang
- Zhi-Qiang Zou, Li Wang, Ji-Guang Yu, Infectious Disease Hospital of Yantai, Yantai 264001, Shandong Province, China
| | - Ji-Guang Yu
- Zhi-Qiang Zou, Li Wang, Ji-Guang Yu, Infectious Disease Hospital of Yantai, Yantai 264001, Shandong Province, China
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Abstract
The liver is an organ that has the largest amount of natural killer T(NKT) cells, which play critical roles in the pathogenesis of liver diseases. In this article, the authors summarize recent findings about the roles of NKT cells in liver injury, inflammation, fibrosis, regeneration and cancer. In brief, NKT cells accelerate liver injury by producing pro-inflammatory cytokines and directly killing hepatocytes. NKT cells are involved in complex roles in liver fibrogenesis. For instance, NKT cells inhibit liver fibrosis via suppressing hepatic stellate cell activation and can also promote liver fibrosis via enhancing liver inflammation and injury. Inactivated or weakly activated NKT cells play a minimal role in controlling liver regeneration, whilst activated NKT cells have an inhibitory effect on liver regeneration. In liver cancer, NKT cells play both pro-tumor and anti-tumor roles in controlling tumor progress.
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Affiliation(s)
- Hua Wang
- Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Hefei, 230032, China
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29
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Li M, Zhou ZH, Sun XH, Zhang X, Zhu XJ, Jin SG, Jiang Y, Gao YT, Li CZ, Gao YQ. The dynamic changes of circulating invariant natural killer T cells during chronic hepatitis B virus infection. Hepatol Int 2016; 10:594-601. [PMID: 26924524 DOI: 10.1007/s12072-015-9650-0] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2015] [Accepted: 07/05/2015] [Indexed: 01/04/2023]
Abstract
AIM The protective role of invariant natural killer T cells (iNKTs) against hepatitis B virus (HBV) infection remains controversial. We sought to clarify the role of peripheral iNKT cells during chronic HBV infection. METHODS Sixty patients with chronic HBV infection were categorized into an immune tolerance phase (HBV-IT) (n = 16), an immune clearance phase (HBV-IC) (n = 19) and an inactive carrier phase (HBV-IA) (n = 25). Twenty healthy individuals were enrolled as healthy controls. Another 21 HBeAg-positive patients were administrated with entecavir (0.5 mg/day) for 6 months. The percentages of circulating iNKT cells and their IFN-γ and IL-4 expression levels were examined by flow cytometry. The relationships between serum HBV DNA, ALT levels, the percentages of iNKT cells, and their IFN-γ and IL-4 levels were analyzed. RESULTS Compared to healthy controls, the percentage of iNKT cells decreased in HBV-IT, but increased in HBV-IC and HBV-IA. Circulating IFN-γ-producing iNKT cells gradually increased, whereas IL-4-producing iNKT cells gradually decreased from HBV-IT stage to HBV-IC and HBV-IA stages. The frequency of iNKT cells and their IFN-γ levels were reversely correlated with viral load. The levels of IL-4 expressed by iNKT cells were positively correlated to viral load and the serum ALT levels. After anti-virus therapy, the percentage of IFN-γ-producing iNKT cells increased while the percentage of IL-4-producing iNKT cells decreased. CONCLUSIONS During chronic HBV infection, the percentages of peripheral iNKT cells and its cytokines expressions of IFN-γ and IL-4 showed dynamic changes. The expression levels of IFN-γ and IL-4 were correlated with the clearance of HBV and liver injury.
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Affiliation(s)
- Man Li
- Laboratory of Cellular Immunity, Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shuguang Hospital, Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People's Republic of China
| | - Zhen-Hua Zhou
- Laboratory of Cellular Immunity, Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shuguang Hospital, Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People's Republic of China
| | - Xue-Hua Sun
- Department of Hepatopathy, Shuguang Hospital, Affiliated to Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai, 201203, People's Republic of China
| | - Xin Zhang
- Laboratory of Cellular Immunity, Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shuguang Hospital, Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People's Republic of China
| | - Xiao-Jun Zhu
- Department of Hepatopathy, Shuguang Hospital, Affiliated to Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai, 201203, People's Republic of China
| | - Shu-Gen Jin
- Laboratory of Cellular Immunity, Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shuguang Hospital, Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People's Republic of China
| | - Yun Jiang
- Department of Hepatopathy, Shuguang Hospital, Affiliated to Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai, 201203, People's Republic of China
| | - Ya-Ting Gao
- Laboratory of Cellular Immunity, Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shuguang Hospital, Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People's Republic of China
| | - Cheng-Zhong Li
- Department of Infectious Diseases, Changhai Hospital, Second Military Medical University, Shanghai, 200433, People's Republic of China.
| | - Yue-Qiu Gao
- Laboratory of Cellular Immunity, Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shuguang Hospital, Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People's Republic of China. .,Department of Hepatopathy, Shuguang Hospital, Affiliated to Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai, 201203, People's Republic of China.
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30
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Wen X, Kim S, Xiong R, Li M, Lawrenczyk A, Huang X, Chen SY, Rao P, Besra GS, Dellabona P, Casorati G, Porcelli SA, Akbari O, Exley MA, Yuan W. A Subset of CD8αβ+ Invariant NKT Cells in a Humanized Mouse Model. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2015; 195:1459-69. [PMID: 26157173 PMCID: PMC4530047 DOI: 10.4049/jimmunol.1500574] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/13/2015] [Accepted: 06/12/2015] [Indexed: 11/19/2022]
Abstract
Invariant NKT (iNKT) cells are unconventional innate-like T cells demonstrating potent antitumor function in conventional mouse models. However, the iNKT cell ligands have had limited efficacy in human antitumor clinical trials, mostly due to the profound differences in the properties and compositions of iNKT cells between the two species, including the presence of a CD8(+) subset of iNKT cells only in humans. To build reliable in vivo models for studying human iNKT cells, we recently developed the first humanized mouse model (hCD1d-KI) with human CD1d knocked in. To further humanize the mouse model, we now introduced the human invariant NKT TCRα-chain (Vα24Jα18) into the hCD1d-knockin mice. Similar to humans, this humanized mouse model developed a subset of CD8αβ(+) iNKT cells among other human-like iNKT subsets. The presence of the CD8αβ(+) iNKT cells in the thymus suggests that these cells developed in the thymus. In the periphery, these NKT cells showed a strong Th1-biased cytokine response and potent cytotoxicity for syngeneic tumor cells upon activation, as do human CD8αβ(+) iNKT cells. The low binding avidity of iNKT TCRs to the human CD1d/lipid complex and high prevalence of Vβ7 TCRβ among the CD8(+) iNKT cells strongly point to a low avidity-based developmental program for these iNKT cells, which included the suppression of Th-POK and upregulation of eomesodermin transcriptional factors. Our establishment of this extensively humanized mouse model phenotypically and functionally reflecting the human CD1d/iNKT TCR system will greatly facilitate the future design and optimization of iNKT cell-based immunotherapies.
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MESH Headings
- Animals
- Antigens, CD1d/genetics
- Antigens, CD1d/metabolism
- CD8 Antigens/metabolism
- Cytotoxicity, Immunologic
- Humans
- Immunologic Memory
- Immunophenotyping
- Mice
- Mice, Knockout
- Models, Animal
- Natural Killer T-Cells/immunology
- Natural Killer T-Cells/metabolism
- Phenotype
- Protein Binding
- Receptors, Antigen, T-Cell/metabolism
- Receptors, Antigen, T-Cell, alpha-beta/metabolism
- T-Lymphocyte Subsets/immunology
- T-Lymphocyte Subsets/metabolism
- Transcription, Genetic
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Affiliation(s)
- Xiangshu Wen
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033
| | - Seil Kim
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033
| | - Ran Xiong
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033
| | - Michelle Li
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033
| | - Agnieszka Lawrenczyk
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033
| | - Xue Huang
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033
| | - Si-Yi Chen
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033
| | - Ping Rao
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033
| | - Gurdyal S Besra
- School of Biosciences, University of Birmingham, Birmingham B15 2TT, United Kingdom
| | - Paolo Dellabona
- Experimental Immunology Unit, Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, 20134 Milano, Italy
| | - Giulia Casorati
- Experimental Immunology Unit, Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, 20134 Milano, Italy
| | - Steven A Porcelli
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461
| | - Omid Akbari
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033
| | - Mark A Exley
- Faculty of Medical and Human Sciences, Manchester Collaborative Centre for Inflammation Research, University of Manchester, Manchester M13 9NT, United Kingdom; and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115
| | - Weiming Yuan
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033;
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31
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Opasawatchai A, Matangkasombut P. iNKT Cells and Their Potential Lipid Ligands during Viral Infection. Front Immunol 2015; 6:378. [PMID: 26257744 PMCID: PMC4513233 DOI: 10.3389/fimmu.2015.00378] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2015] [Accepted: 07/11/2015] [Indexed: 01/12/2023] Open
Abstract
Invariant natural killer T (iNKT) cells are a unique population of lipid-reactive CD1d-restricted innate-like T lymphocytes. Despite being a minor population, they serve as an early source of cytokines and promote immunological crosstalk thus bridging innate and adaptive immunity. Diseases ranging from allergy, autoimmunity, and cancer, as well as infectious diseases, including viral infection, have been reported to be influenced by iNKT cells. However, it remains unclear how iNKT cells are activated during viral infection, as virus-derived lipid antigens have not been reported. Cytokines may activate iNKT cells during infections from influenza and murine cytomegalovirus, although CD1d-dependent activation is evident in other viral infections. Several viruses, such as dengue virus, induce CD1d upregulation, which correlates with iNKT cell activation. In contrast, herpes simplex virus type 1 (HSV-1), human immunodeficiency virus (HIV), Epstein–Barr virus, and human papilloma virus promote CD1d downregulation as a strategy to evade iNKT cell recognition. These observations suggest the participation of a CD1d-dependent process in the activation of iNKT cells in response to viral infection. Endogenous lipid ligands, including phospholipids as well as glycosphingolipids, such as glucosylceramide, have been proposed to mediate iNKT cell activation. Pro-inflammatory signals produced during viral infection may stimulate iNKT cells through enhanced CD1d-dependent endogenous lipid presentation. Furthermore, viral infection may alter lipid composition and inhibit endogenous lipid degradation. Recent advances in this field are reviewed.
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Affiliation(s)
- Anunya Opasawatchai
- Department of Microbiology, Faculty of Science, Mahidol University , Bangkok , Thailand ; Faculty of Dentistry, Mahidol University , Bangkok , Thailand
| | - Ponpan Matangkasombut
- Department of Microbiology, Faculty of Science, Mahidol University , Bangkok , Thailand ; Systems Biology of Diseases Research Unit, Faculty of Science, Mahidol University , Bangkok , Thailand
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32
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de Oliveira FL, Gatto M, Bassi N, Luisetto R, Ghirardello A, Punzi L, Doria A. Galectin-3 in autoimmunity and autoimmune diseases. Exp Biol Med (Maywood) 2015; 240:1019-28. [PMID: 26142116 DOI: 10.1177/1535370215593826] [Citation(s) in RCA: 121] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Galectin-3 (gal-3) is a β-galactoside-binding lectin, which regulates cell-cell and extracellular interactions during self/non-self-antigen recognition and cellular activation, proliferation, differentiation, migration and apoptosis. It plays a significant role in cellular and tissue pathophysiology by organizing niches that drive inflammation and immune responses. Gal-3 has some therapeutic potential in several diseases, including chronic inflammatory disorders, cancer and autoimmune diseases. Gal-3 exerts a broad spectrum of functions which differs according to its intra- or extracellular localization. Recombinant gal-3 strategy has been used to identify potential mode of action of gal-3; however, exogenous gal-3 may not reproduce the functions of the endogenous gal-3. Notably, gal-3 induces monocyte-macrophage differentiation, interferes with dendritic cell fate decision, regulates apoptosis on T lymphocytes and inhibits B-lymphocyte differentiation into immunoglobulin secreting plasma cells. Considering the influence of these cell populations in the pathogenesis of several autoimmune diseases, gal-3 seems to play a role in development of autoimmunity. Gal-3 has been suggested as a potential therapeutic agent in patients affected with some autoimmune disorders. However, the precise role of gal-3 in driving the inflammatory process in autoimmune or immune-mediated disorders remains elusive. Here, we reviewed the involvement of gal-3 in cellular and tissue events during autoimmune and immune-mediated inflammatory diseases.
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Affiliation(s)
- Felipe L de Oliveira
- Coimbra Group Fellowship for Latin American Professors, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ CEP 21941-902, Brazil Rheumatology Unit, Department of Medicine, University of Padova, Padova 35128, Italy
| | - Mariele Gatto
- Rheumatology Unit, Department of Medicine, University of Padova, Padova 35128, Italy
| | - Nicola Bassi
- Rheumatology Unit, Department of Medicine, University of Padova, Padova 35128, Italy
| | - Roberto Luisetto
- Rheumatology Unit, Department of Medicine, University of Padova, Padova 35128, Italy
| | - Anna Ghirardello
- Rheumatology Unit, Department of Medicine, University of Padova, Padova 35128, Italy
| | - Leonardo Punzi
- Rheumatology Unit, Department of Medicine, University of Padova, Padova 35128, Italy
| | - Andrea Doria
- Rheumatology Unit, Department of Medicine, University of Padova, Padova 35128, Italy
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33
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Zhu H, Zhang Y, Liu H, Zhang Y, Kang Y, Mao R, Yang F, Zhou D, Zhang J. Preserved Function of Circulating Invariant Natural Killer T Cells in Patients With Chronic Hepatitis B Virus Infection. Medicine (Baltimore) 2015; 94:e961. [PMID: 26091463 PMCID: PMC4616535 DOI: 10.1097/md.0000000000000961] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
To date, the role of invariant natural killer T (iNKT) cells in chronic hepatitis B virus (HBV) infection is not fully understood. In previous reports, iNKT cells were identified by indirect methods. However, discrepancies regarding the prevalence and function of iNKT cells during HBV infection were observed. In this study, we have devised a direct, highly specific CD1d tetramer-based methodology to test whether patients with HBV infection have associated iNKT-cell defects. In our study, a total of 93 chronic HBV-infected patients and 30 healthy individuals (as control) were enrolled. The prevalence of iNKT cells, their cytokine producing capacity, and in vitro expansion were determined by flow cytometric analysis with CD1d tetramer staining. Our observation demonstrated that there was no significant difference in circulating CD1d-tetramer positive iNKT cell numbers between HBV-infected patients and healthy controls. The capacity of iNKT cells to produce IFN-γ or IL-4 as well as their in vitro expansion was also comparable between these 2 groups. However, among chronic HBV-infected patients, a decrease in iNKT cell-number was observed in chronic hepatitis B (CHB) and cirrhosis patients in comparison to that in immune tolerant (IT) patients. These results indicated that patients with chronic HBV infection may have normal prevalence and preserved function of circulating iNKT cells. And antiviral therapy with nucleot(s)ide analogue does not alter the frequency and function of circulating iNKT cells in chronic Hepatitis B patients.
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Affiliation(s)
- Haoxiang Zhu
- From the Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China (HZ, YZ, HL, YZ, YK, RM, FY, JZ); Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA (DZ); and Key laboratory of Medical Molecular Virology of the Ministries of Education and Health (MOH&MOE), Shanghai Medical College, Fudan University, Shanghai, China (JZ)
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34
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Slauenwhite D, Johnston B. Regulation of NKT Cell Localization in Homeostasis and Infection. Front Immunol 2015; 6:255. [PMID: 26074921 PMCID: PMC4445310 DOI: 10.3389/fimmu.2015.00255] [Citation(s) in RCA: 74] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2015] [Accepted: 05/07/2015] [Indexed: 01/23/2023] Open
Abstract
Natural killer T (NKT) cells are a specialized subset of T lymphocytes that regulate immune responses in the context of autoimmunity, cancer, and microbial infection. Lipid antigens derived from bacteria, parasites, and fungi can be presented by CD1d molecules and recognized by the canonical T cell receptors on NKT cells. Alternatively, NKT cells can be activated through recognition of self-lipids and/or pro-inflammatory cytokines generated during infection. Unlike conventional T cells, only a small subset of NKT cells traffic through the lymph nodes under homeostatic conditions, with the largest NKT cell populations localizing to the liver, lungs, spleen, and bone marrow. This is thought to be mediated by differences in chemokine receptor expression profiles. However, the impact of infection on the tissue localization and function of NKT remains largely unstudied. This review focuses on the mechanisms mediating the establishment of peripheral NKT cell populations during homeostasis and how tissue localization of NKT cells is affected during infection.
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Affiliation(s)
- Drew Slauenwhite
- Department of Microbiology and Immunology, Dalhousie University , Halifax, NS , Canada
| | - Brent Johnston
- Department of Microbiology and Immunology, Dalhousie University , Halifax, NS , Canada ; Department of Pediatrics, Dalhousie University , Halifax, NS , Canada ; Department of Pathology, Dalhousie University , Halifax, NS , Canada ; Beatrice Hunter Cancer Research Institute , Halifax, NS , Canada
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35
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Duval F, Moreno-Cuevas JE, González-Garza MT, Maldonado-Bernal C, Cruz-Vega DE. Liver fibrosis and mechanisms of the protective action of medicinal plants targeting inflammation and the immune response. Int J Inflam 2015; 2015:943497. [PMID: 25954568 PMCID: PMC4411506 DOI: 10.1155/2015/943497] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2014] [Accepted: 11/29/2014] [Indexed: 12/12/2022] Open
Abstract
Inflammation is a central feature of liver fibrosis as suggested by its role in the activation of hepatic stellate cells leading to extracellular matrix deposition. During liver injury, inflammatory cells are recruited in the injurious site through chemokines attraction. Thus, inflammation could be a target to reduce liver fibrosis. The pandemic trend of obesity, combined with the high incidence of alcohol intake and viral hepatitis infections, highlights the urgent need to find accessible antifibrotic therapies. Medicinal plants are achieving popularity as antifibrotic agents, supported by their safety, cost-effectiveness, and versatility. The aim of this review is to describe the role of inflammation and the immune response in the pathogenesis of liver fibrosis and detail the mechanisms of inhibition of both events by medicinal plants in order to reduce liver fibrosis.
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Affiliation(s)
- Florent Duval
- Catedra de Terapia Celular, Escuela de Medicina, Tecnológico de Monterrey, Avenida Morones Prieto 3000 Pte., 64710 Monterrey, NL, Mexico
| | - Jorge E. Moreno-Cuevas
- Catedra de Terapia Celular, Escuela de Medicina, Tecnológico de Monterrey, Avenida Morones Prieto 3000 Pte., 64710 Monterrey, NL, Mexico
| | - María Teresa González-Garza
- Catedra de Terapia Celular, Escuela de Medicina, Tecnológico de Monterrey, Avenida Morones Prieto 3000 Pte., 64710 Monterrey, NL, Mexico
| | - Carmen Maldonado-Bernal
- Laboratorio de Investigación en Inmunología y Proteómica, Hospital Infantil de México Federico Gómez, Calle Dr. Márquez 162, 06720 Ciudad de México, DF, Mexico
| | - Delia Elva Cruz-Vega
- Catedra de Terapia Celular, Escuela de Medicina, Tecnológico de Monterrey, Avenida Morones Prieto 3000 Pte., 64710 Monterrey, NL, Mexico
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Kawada N, Parola M. Interactions of Stellate Cells with Other Non-Parenchymal Cells. STELLATE CELLS IN HEALTH AND DISEASE 2015:185-207. [DOI: 10.1016/b978-0-12-800134-9.00012-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Tincati C, Basilissi M, Sinigaglia E, Merlini E, Carpani G, Monforte AD, Marchetti G. Invariant natural killer T (iNKT) cells in HAART-treated, HIV-positive patients with bone and cardiovascular impairment. PLoS One 2014; 9:e110287. [PMID: 25329381 PMCID: PMC4201495 DOI: 10.1371/journal.pone.0110287] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2014] [Accepted: 09/16/2014] [Indexed: 11/19/2022] Open
Abstract
Background Invariant Natural Killer T (iNKT) cells represent a determinant in the course of infections and diseases, however, their role in the pathogenesis of non-infectious co-morbidities in HIV-positive patients is unknown. Methods Flow cytometry was used to investigate iNKT cell frequency, phenotype and function in HIV-infected patients on HAART with bone and/or cardiovascular disorders and in HIV-positive controls free from co-morbidities. Results iNKT cells from subjects with bone and cardiovascular impairment expressed high levels of CD161 and predominantly secreted TNF. iNKT cells from individuals with bone disease alone did not show any distinctive phenotypical or functional characteristics. The functional capacity of iNKT cells in patients with cardiovascular disorder was impaired with no cytokine release upon stimulation. Conclusion iNKT cells may have a role in non-infectious co-morbidities in treated HIV disease, possibly through the exacerbation of inflammation. Further studies are needed to investigate iNKT cells in the pathogenesis of non-communicable disorders in HIV infection.
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Affiliation(s)
- Camilla Tincati
- Department of Health Sciences, Clinic of Infectious Diseases and Tropical Medicine, “San Paolo” Hospital, University of Milan, Milan, Italy
| | - Matteo Basilissi
- Department of Health Sciences, Clinic of Infectious Diseases and Tropical Medicine, “San Paolo” Hospital, University of Milan, Milan, Italy
| | | | - Esther Merlini
- Department of Health Sciences, Clinic of Infectious Diseases and Tropical Medicine, “San Paolo” Hospital, University of Milan, Milan, Italy
| | | | - Antonella d’Arminio Monforte
- Department of Health Sciences, Clinic of Infectious Diseases and Tropical Medicine, “San Paolo” Hospital, University of Milan, Milan, Italy
| | - Giulia Marchetti
- Department of Health Sciences, Clinic of Infectious Diseases and Tropical Medicine, “San Paolo” Hospital, University of Milan, Milan, Italy
- * E-mail:
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Czaja AJ. Review article: chemokines as orchestrators of autoimmune hepatitis and potential therapeutic targets. Aliment Pharmacol Ther 2014; 40:261-79. [PMID: 24890045 DOI: 10.1111/apt.12825] [Citation(s) in RCA: 61] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2014] [Revised: 04/10/2014] [Accepted: 05/14/2014] [Indexed: 12/17/2022]
Abstract
BACKGROUND Chemokines contribute to the pathogenesis of autoimmune hepatitis by directing the migration and positioning of inflammatory and immune cells within the liver. AIM Describe the liver-infiltrating effector cell populations in autoimmune hepatitis, indicate the chemokines that influence their migration, describe the role of chemokines in hepatic fibrosis and identify chemokine-directed treatment opportunities. METHODS Studies cited in Pub Med from 1972 to 2014 for autoimmune hepatitis, chemokines in liver disease, pathogenesis of autoimmune hepatitis and chemokine therapy were selected. RESULTS T helper type 17 lymphocytes expressing CXCR3 and CCR6 are attracted to the liver by the secretion of CXCL9, CXCL10 and CXCL11. These cells recruit pro-inflammatory T helper type 1 lymphocytes expressing CXCR3 and CCR5 by secreting CXCL10. Resident natural killer T cells expressing CXCR6 migrate in response to the local secretion of CXCL16, and they modulate the inflammatory response. T helper type 2 lymphocytes expressing CCR4 are attracted by CCL17 and CCL22, and they dampen the expansion of pro-inflammatory cells. Regulatory T cells expressing CXCR3 are attracted by the secretion of CXCL9, and they help dampen the pro-inflammatory responses. CCL2, CCL3, CCL5, CXCL4, CXCL10 and CXCL16 promote fibrosis by activating or attracting hepatic stellate cells, and CX3CL1 may prevent fibrosis by affecting the apoptosis of monocytes. CONCLUSIONS Chemokines are requisites for mobilising, directing and positioning the effector cells in immune-mediated liver disease. They are feasible therapeutic targets in autoimmune hepatitis, and the evaluation of monoclonal antibodies that neutralise the pro-inflammatory ligands or designer peptides that block receptor activity are investigational opportunities.
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Affiliation(s)
- A J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN, USA
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Tu T, Budzinska MA, Maczurek AE, Cheng R, Di Bartolomeo A, Warner FJ, McCaughan GW, McLennan SV, Shackel NA. Novel aspects of the liver microenvironment in hepatocellular carcinoma pathogenesis and development. Int J Mol Sci 2014; 15:9422-58. [PMID: 24871369 PMCID: PMC4100103 DOI: 10.3390/ijms15069422] [Citation(s) in RCA: 63] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2014] [Revised: 05/13/2014] [Accepted: 05/14/2014] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a prevalent primary liver cancer that is derived from hepatocytes and is characterised by high mortality rate and poor prognosis. While HCC is driven by cumulative changes in the hepatocyte genome, it is increasingly recognised that the liver microenvironment plays a pivotal role in HCC propensity, progression and treatment response. The microenvironmental stimuli that have been recognised as being involved in HCC pathogenesis are diverse and include intrahepatic cell subpopulations, such as immune and stellate cells, pathogens, such as hepatitis viruses, and non-cellular factors, such as abnormal extracellular matrix (ECM) and tissue hypoxia. Recently, a number of novel environmental influences have been shown to have an equally dramatic, but previously unrecognized, role in HCC progression. Novel aspects, including diet, gastrointestinal tract (GIT) microflora and circulating microvesicles, are now being recognized as increasingly important in HCC pathogenesis. This review will outline aspects of the HCC microenvironment, including the potential role of GIT microflora and microvesicles, in providing new insights into tumourigenesis and identifying potential novel targets in the treatment of HCC.
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Affiliation(s)
- Thomas Tu
- Liver Cell Biology, Centenary Institute, Sydney, NSW 2050, Australia.
| | | | | | - Robert Cheng
- Liver Cell Biology, Centenary Institute, Sydney, NSW 2050, Australia.
| | - Anna Di Bartolomeo
- School of Medicine, University of Adelaide, Adelaide, SA 5005, Australia.
| | - Fiona J Warner
- Liver Cell Biology, Centenary Institute, Sydney, NSW 2050, Australia.
| | | | - Susan V McLennan
- Sydney Medical School, University of Sydney, Sydney, NSW 2006, Australia.
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Involvement of DNA damage response pathways in hepatocellular carcinoma. BIOMED RESEARCH INTERNATIONAL 2014; 2014:153867. [PMID: 24877058 PMCID: PMC4022277 DOI: 10.1155/2014/153867] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/08/2013] [Revised: 01/23/2014] [Accepted: 03/25/2014] [Indexed: 12/16/2022]
Abstract
Hepatocellular carcinoma (HCC) has been known as one of the most lethal human malignancies, due to the difficulty of early detection, chemoresistance, and radioresistance, and is characterized by active angiogenesis and metastasis, which account for rapid recurrence and poor survival. Its development has been closely associated with multiple risk factors, including hepatitis B and C virus infection, alcohol consumption, obesity, and diet contamination. Genetic alterations and genomic instability, probably resulted from unrepaired DNA lesions, are increasingly recognized as a common feature of human HCC. Dysregulation of DNA damage repair and signaling to cell cycle checkpoints, known as the DNA damage response (DDR), is associated with a predisposition to cancer and affects responses to DNA-damaging anticancer therapy. It has been demonstrated that various HCC-associated risk factors are able to promote DNA damages, formation of DNA adducts, and chromosomal aberrations. Hence, alterations in the DDR pathways may accumulate these lesions to trigger hepatocarcinogenesis and also to facilitate advanced HCC progression. This review collects some of the most known information about the link between HCC-associated risk factors and DDR pathways in HCC. Hopefully, the review will remind the researchers and clinicians of further characterizing and validating the roles of these DDR pathways in HCC.
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Cellular and molecular mechanisms in liver fibrogenesis. Arch Biochem Biophys 2014; 548:20-37. [PMID: 24631571 DOI: 10.1016/j.abb.2014.02.015] [Citation(s) in RCA: 151] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2013] [Revised: 02/07/2014] [Accepted: 02/26/2014] [Indexed: 02/07/2023]
Abstract
Liver fibrogenesis is a dynamic and highly integrated molecular, tissue and cellular process, potentially reversible, that drives the progression of chronic liver diseases (CLD) towards liver cirrhosis and hepatic failure. Hepatic myofibroblasts (MFs), the pro-fibrogenic effector cells, originate mainly from activation of hepatic stellate cells and portal fibroblasts being characterized by a proliferative and survival attitude. MFs also contract in response to vasoactive agents, sustain angiogenesis and recruit and modulate activity of cells of innate or adaptive immunity. Chronic activation of wound healing and oxidative stress as well as derangement of epithelial-mesenchymal interactions are "major" pro-fibrogenic mechanisms, whatever the etiology. However, literature has outlined a complex network of pro-fibrogenic factors and mediators proposed to modulate CLD progression, with some of them being at present highly debated in the field, including the role of epithelial to mesenchymal transition and Hedgehog signaling pathways. Hypoxia and angiogenesis as well as inflammasomes are recently emerged as ubiquitous pro-inflammatory and pro-fibrogenic determinants whereas adipokines are mostly involved in CLD related to metabolic disturbances (metabolic syndrome and/or obesity and type 2 diabetes). Finally, autophagy as well as natural killer and natural killer-T cells have been recently proposed to significantly affect fibrogenic CLD progression.
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Han Q, Lan P, Zhang J, Zhang C, Tian Z. Reversal of hepatitis B virus-induced systemic immune tolerance by intrinsic innate immune stimulation. J Gastroenterol Hepatol 2013; 28 Suppl 1:132-7. [PMID: 23855309 DOI: 10.1111/jgh.12034] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/15/2012] [Indexed: 12/19/2022]
Abstract
Systemic immune tolerance induced by chronic hepatitis B virus (HBV) infection is a significant question, but the mechanism of which remains unclear. In this mini-review, we summarize the impaired innate and adaptive immune responses involved in immune tolerance in chronic HBV infection. Furthermore, we delineate a novel dual functional small RNA to inhibit HBV replication and stimulate innate immunity against HBV, which proposed a promising immunotherapeutic intervention to interrupt HBV-induced immunotolerance. A mouse model of HBV persistence was established and used to observe the immune tolerant to HBV vaccination, the cell-intrinsic immune tolerance of which might be reversed by chemically synthesized dual functional small RNA (3p-hepatitis B Virus X gene [HBx]-small interfering RNA) in vitro experiments and by biologically constructed dual functional vector (single-stranded RNA-HBx- short hairpin RNA) in vivo experiment using HBV-carrier mice.
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Affiliation(s)
- Qiuju Han
- Institute of Immunopharmacology and Immunotherapy, School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong, China
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Yanagisawa K, Yue S, van der Vliet HJ, Wang R, Alatrakchi N, Golden-Mason L, Schuppan D, Koziel MJ, Rosen HR, Exley MA. Ex vivo analysis of resident hepatic pro-inflammatory CD1d-reactive T cells and hepatocyte surface CD1d expression in hepatitis C. J Viral Hepat 2013; 20:556-65. [PMID: 23808994 PMCID: PMC4054599 DOI: 10.1111/jvh.12081] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2012] [Accepted: 12/12/2012] [Indexed: 12/20/2022]
Abstract
Hepatic CD1d-restricted and natural killer T-cell populations are heterogeneous. Classical 'type 1' α-galactosylceramide-reactive CD1d-restricted T cells express 'invariant' TCRα ('iNKT'). iNKT dominating rodent liver are implicated in inflammation, including in hepatitis models. Low levels of iNKT are detected in human liver, decreased in subjects with chronic hepatitis C (CHC). However, high levels of human hepatic CD161(±) CD56(±) noninvariant pro-inflammatory CD1d-restricted 'type 2' T cells have been identified in vitro. Unlike rodents, healthy human hepatocytes only express trace and intracellular CD1d. Total hepatic CD1d appears to be increased in CHC and primary biliary cirrhosis. Direct ex vivo analysis of human intrahepatic lymphocytes (IHL), including matched ex vivo versus in vitro expanded IHL, demonstrated detectable noninvariant CD1d reactivity in substantial proportions of HCV-positive livers and significant fractions of HCV-negative livers. However, α-galactosylceramide-reactive iNKT were detected only relatively rarely. Liver CD1d-restricted IHL produced IFNγ, variable levels of IL-10 and modest levels of Th2 cytokines IL-4 and IL-13 ex vivo. In a novel FACS assay, a major fraction (10-20%) of hepatic T cells rapidly produced IFNγ and up-regulated activation marker CD69 in response to CD1d. As previously only shown with murine iNKT, noninvariant human CD1d-specific responses were also augmented by IL-12. Interestingly, CD1d was found selectively expressed on the surface of hepatocytes in CHC, but not those CHC subjects with history of alcohol usage or resolved CHC. In contrast to hepatic iNKT, noninvariant IFNγ-producing type 2 CD1d-reactive NKT cells are commonly detected in CHC, together with cognate ligand CD1d, implicating them in CHC liver damage.
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Affiliation(s)
- Kazuhiko Yanagisawa
- Medicine; Beth Israel Deaconess Medical Ctr; Harvard Medical School, Boston, MA
| | - Simon Yue
- Medicine; Beth Israel Deaconess Medical Ctr; Harvard Medical School, Boston, MA
| | | | - RuoJie Wang
- Medicine; Beth Israel Deaconess Medical Ctr; Harvard Medical School, Boston, MA
| | - Nadia Alatrakchi
- Medicine; Beth Israel Deaconess Medical Ctr; Harvard Medical School, Boston, MA
| | - Lucy Golden-Mason
- Gastroenterology/Hepatology, University of Colorado Denver Health Sciences Center, Denver, CO
| | - Detlef Schuppan
- Medicine; Beth Israel Deaconess Medical Ctr; Harvard Medical School, Boston, MA
| | - Margaret J. Koziel
- Medicine; Beth Israel Deaconess Medical Ctr; Harvard Medical School, Boston, MA
| | - Hugo R. Rosen
- Gastroenterology/Hepatology, University of Colorado Denver Health Sciences Center, Denver, CO
| | - Mark A. Exley
- Medicine; Beth Israel Deaconess Medical Ctr; Harvard Medical School, Boston, MA
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Gao B, Radaeva S. Natural killer and natural killer T cells in liver fibrosis. BIOCHIMICA ET BIOPHYSICA ACTA 2013; 1832:1061-9. [PMID: 23022478 PMCID: PMC3552008 DOI: 10.1016/j.bbadis.2012.09.008] [Citation(s) in RCA: 114] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/09/2012] [Accepted: 09/20/2012] [Indexed: 12/22/2022]
Abstract
The liver lymphocyte population is enriched with natural killer (NK) cells, which play a key role in host defense against viral infection and tumor transformation. Recent evidence from animal models suggests that NK cells also play an important role in inhibiting liver fibrosis by selectively killing early or senescence activated hepatic stellate cells (HSCs) and by producing the anti-fibrotic cytokine IFN-γ. Furthermore, clinical studies have revealed that human NK cells can kill primary human HSCs and that the ability of NK cells from HCV patients to kill HSCs is enhanced and correlates inversely with the stages of liver fibrosis. IFN-α treatment enhances, while other factors (e.g., alcohol, TGF-β) attenuate, the cytotoxicity of NK cells against HSCs, thereby differentially regulating liver fibrogenesis. In addition, the mouse liver lymphocyte population is also enriched for natural killer T (NKT) cells, whereas human liver lymphocytes have a much lower percentage of NKT cells. Many studies suggest that NKT cells promote liver fibrogenesis by producing pro-fibrotic cytokines such as IL-4, IL-13, hedgehog ligands, and osteopontin; however, NKT cells may also attenuate liver fibrosis under certain conditions by killing HSCs and by producing IFN-γ. Finally, the potential for NK and NKT cells to be used as therapeutic targets for anti-fibrotic therapy is discussed. This article is part of a Special Issue entitled: Fibrosis: Translation of basic research to human disease.
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Affiliation(s)
- Bin Gao
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA.
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45
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Wehr A, Baeck C, Heymann F, Niemietz PM, Hammerich L, Martin C, Zimmermann HW, Pack O, Gassler N, Hittatiya K, Ludwig A, Luedde T, Trautwein C, Tacke F. Chemokine receptor CXCR6-dependent hepatic NK T Cell accumulation promotes inflammation and liver fibrosis. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2013; 190:5226-5236. [PMID: 23596313 DOI: 10.4049/jimmunol.1202909] [Citation(s) in RCA: 210] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Chronic liver injury characteristically results in hepatic inflammation, which represents a prerequisite for organ fibrosis. Although NKT cells are abundantly present in liver and involved in hepatic inflammation, molecular mechanisms of their recruitment in liver fibrosis remained elusive. We hypothesized that chemokine receptor CXCR6 and its ligand CXCL16 control NKT cell migration and functionality in liver fibrosis. In patients with chronic liver diseases (n = 58), CXCR6 and CXCL16 expression was intrahepatically upregulated compared with controls. In murine liver, Cxcl16 was strongly expressed by endothelium and macrophages, whereas lymphocyte populations (NKT, NK, CD4 T, CD8 T cells) expressed CXCR6. Intravital two-photon microscopy imaging of Cxcr6(+/gfp) and Cxcr6(gfp/gfp) mice and chemotaxis studies in vitro revealed that CXCR6 specifically controls hepatic NKT cell accumulation during the early response upon experimental liver damage. Hepatic invariant NKT cells expressed distinct proinflammatory cytokines including IFN-γ and IL-4 upon injury. CXCR6-deficient mice were protected from liver fibrosis progression in two independent experimental models. Macrophage infiltration and protein levels of inflammatory cytokines IFN-γ, TNF-α, and IL-4 were also reduced in fibrotic livers of Cxcr6(-/-) mice, corroborating that hepatic NKT cells provide essential cytokine signals perpetuating hepatic inflammation and fibrogenesis. Adoptive transfer of NKT cells, but not CD4 T cells, isolated from wild type livers restored hepatic fibrosis in Cxcr6(-/-) mice upon experimental steatohepatitis. Our results demonstrate that hepatic NKT cells accumulate CXCR6-dependent early upon injury, thereby accentuating the inflammatory response in the liver and promoting hepatic fibrogenesis. Interfering with CXCR6/CXCL16 might therefore bear therapeutic potential in liver fibrosis.
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Affiliation(s)
- Alexander Wehr
- Department of Medicine III, University-Hospital Aachen, 52074 Aachen, Germany
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Abstract
Natural killer T (NKT) cells were first recognized more than two decades ago as a distinct lymphocyte lineage that regulates a broad range of immune responses. The activation of NKT cells paradoxically can lead to either suppression or stimulation of immune responses, but despite this uncertainty, many investigators are hopeful that immune therapies can be developed based on NKT cell modulation. To date, the biology of NKT cells is not well characterized and details of their development have only just started to emerge. It remains unclear how NKT cells migrate from the thymus to the peripheral organs and tissues, and in turn play such diverse roles from one type of immune response to another. Despite this, recent advances in intravital microscopy represent a powerful tool for revealing new insights into NKT cellular dynamics, their patrolling and immunoregulatory functions, which could not have been gained by non-microscopy means. Indeed, imaging has revolutionized the way we visualize with exceptional resolution the cells of the immune system. Instead of seeking a comprehensive review of NKT cell biology, this review attempts to highlight some of the recent studies that use in vivo imaging technologies to address NKT cell responses in a variety of animal models.
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Rout N, Greene J, Yue S, O'Connor D, Johnson RP, Else JG, Exley MA, Kaur A. Loss of effector and anti-inflammatory natural killer T lymphocyte function in pathogenic simian immunodeficiency virus infection. PLoS Pathog 2012; 8:e1002928. [PMID: 23028326 PMCID: PMC3447755 DOI: 10.1371/journal.ppat.1002928] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2012] [Accepted: 08/13/2012] [Indexed: 11/29/2022] Open
Abstract
Chronic immune activation is a key determinant of AIDS progression in HIV-infected humans and simian immunodeficiency virus (SIV)-infected macaques but is singularly absent in SIV-infected natural hosts. To investigate whether natural killer T (NKT) lymphocytes contribute to the differential modulation of immune activation in AIDS-susceptible and AIDS-resistant hosts, we compared NKT function in macaques and sooty mangabeys in the absence and presence of SIV infection. Cynomolgus macaques had significantly higher frequencies of circulating invariant NKT lymphocytes compared to both rhesus macaques and AIDS-resistant sooty mangabeys. Despite this difference, mangabey NKT lymphocytes were functionally distinct from both macaque species in their ability to secrete significantly more IFN-γ, IL-13, and IL-17 in response to CD1d/α-galactosylceramide stimulation. While NKT number and function remained intact in SIV-infected mangabeys, there was a profound reduction in NKT activation-induced, but not mitogen-induced, secretion of IFN-γ, IL-2, IL-10, and TGF-β in SIV-infected macaques. SIV-infected macaques also showed a selective decline in CD4+ NKT lymphocytes which correlated significantly with an increase in circulating activated memory CD4+ T lymphocytes. Macaques with lower pre-infection NKT frequencies showed a significantly greater CD4+ T lymphocyte decline post SIV infection. The disparate effect of SIV infection on NKT function in mangabeys and macaques could be a manifestation of their differential susceptibility to AIDS. Alternately, these data also raise the possibility that loss of anti-inflammatory NKT function promotes chronic immune activation in pathogenic SIV infection, while intact NKT function helps to protect natural hosts from developing immunodeficiency and aberrant immune activation. Several African nonhuman primate species such as sooty mangabeys are naturally infected with SIV and maintain high levels of viral replication without developing AIDS. SIV-infected natural hosts do not show evidence of increased chronic immune activation, a feature that distinguishes them from AIDS-susceptible SIV-infected Asian macaques. In this study we compared natural killer T (NKT) lymphocytes, a unique subset of innate T lymphocytes with anti-inflammatory properties, in AIDS-resistant and AIDS-susceptible hosts. Sooty mangabey NKT cells retained normal functionality following SIV infection and were more potent than macaque NKT cells in their ability to produce interferon-γ and secrete anti-inflammatory cytokines. In contrast, NKT cells of SIV-infected macaques were markedly hypo-functional with regards to secretion of anti-inflammatory and effector cytokines and showed an association between loss of CD4+ NKT cells and increased immune activation. These findings suggest that dysfunctional NKT cells may promote increased immune activation in AIDS-susceptible hosts while intact effector and anti-inflammatory NKT cells could help to prevent immunodeficiency and increased immune activation in natural hosts.
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Affiliation(s)
- Namita Rout
- New England Primate Research Center, Harvard Medical School, Southborough, Massachusetts, USA
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Brenndörfer ED, Sällberg M. Hepatitis C virus-mediated modulation of cellular immunity. Arch Immunol Ther Exp (Warsz) 2012; 60:315-29. [PMID: 22911132 DOI: 10.1007/s00005-012-0184-z] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2011] [Accepted: 03/09/2012] [Indexed: 12/14/2022]
Abstract
The hepatitis C virus (HCV) is a major cause of chronic liver disease globally. A chronic infection can result in liver fibrosis, liver cirrhosis, hepatocellular carcinoma and liver failure in a significant ratio of the patients. About 170 million people are currently infected with HCV. Since 80 % of the infected patients develop a chronic infection, HCV has evolved sophisticated escape strategies to evade both the innate and the adaptive immune system. Thus, chronic hepatitis C is characterized by perturbations in the number, subset composition and/or functionality of natural killer cells, natural killer T cells, dendritic cells, macrophages and T cells. The balance between HCV-induced immune evasion and the antiviral immune response results in chronic liver inflammation and consequent immune-mediated liver injury. This review summarizes our current understanding of the HCV-mediated interference with cellular immunity and of the factors resulting in HCV persistence. A profound knowledge about the intrinsic properties of HCV and its effects on intrahepatic immunity is essential to be able to design effective immunotherapies against HCV such as therapeutic HCV vaccines.
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Affiliation(s)
- Erwin Daniel Brenndörfer
- Division of Clinical Microbiology F68, Department of Laboratory Medicine, Karolinska Institutet at Karolinska University Hospital Huddinge, 141 86, Stockholm, Sweden.
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Abstract
Natural killer T cells (NKT cells) represent a subset of T lymphocytes that express natural killer (NK) cell surface markers. A subset of NKT cells, termed invariant NKT cells (iNKT), express a highly restricted T cell receptor (TCR) and respond to CD1d-restricted lipid ligands. iNKT cells are now appreciated to play an important role in linking innate and adaptive immune responses and have been implicated in infectious disease, allergy, asthma, autoimmunity, and tumor surveillance. Advances in iNKT identification and purification have allowed for the detailed study of iNKT activity in both humans and mice during a variety of chronic and acute infections. Comparison of iNKT function between non-pathogenic simian immunodeficiency virus (SIV) infection models and chronic HIV-infected patients implies a role for iNKT activity in controlling immune activation. In vitro studies of influenza infection have revealed novel effector functions of iNKT cells including IL-22 production and modulation of myeloid-derived suppressor cells, but ex vivo characterization of human iNKT cells during influenza infection are lacking. Similarly, as recent evidence suggests iNKT involvement in dengue virus pathogenesis, iNKT cells may modulate responses to a number of emerging pathogens. This Review will summarize current knowledge of iNKT involvement in responses to viral infections in both human and mouse models and will identify critical gaps in knowledge and opportunities for future study. We will also highlight recent efforts to harness iNKT ligands as vaccine adjuvants capable of improving vaccination-induced cellular immune responses.
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Affiliation(s)
- Jennifer A. Juno
- Department of Medical Microbiology, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Yoav Keynan
- Department of Medical Microbiology, University of Manitoba, Winnipeg, Manitoba, Canada
- Department of Community Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada
- Department of Medical Microbiology, University of Nairobi, Nairobi, Kenya
- Department of Internal Medicine, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Keith R. Fowke
- Department of Medical Microbiology, University of Manitoba, Winnipeg, Manitoba, Canada
- Department of Community Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada
- Department of Medical Microbiology, University of Nairobi, Nairobi, Kenya
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Abstract
The incidence of nonalcoholic fatty liver disease is increasing at an astonishing rate in the US population. Although only a small proportion of these patients develop steatohepatitis (NASH), those who do have a greater likelihood of developing end-stage liver disease and complications. Research on liver fibrosis and NASH progression shows that hedgehog (Hh) is reactivated after liver injury to assist in liver repair and regeneration. When the process of tissue repair and regeneration is prolonged or when Hh ligand and related genes are aberrantly regulated and excessive, tissue repair goes awry and NASH progresses to cirrhosis and hepatocellular carcinoma.
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Affiliation(s)
- Brittany N Bohinc
- Department of Endocrinology, Diabetes and Metabolism, Duke University Hospital, Durham, NC 27710, USA
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