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Ali A, Younas K, Khatoon A, Murtaza B, Ji Z, Akbar K, Tanveer Q, Bahadur SUK, Su Z. Immune watchdogs: Tissue-resident lymphocytes as key players in cancer defense. Crit Rev Oncol Hematol 2025; 208:104644. [PMID: 39900319 DOI: 10.1016/j.critrevonc.2025.104644] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Revised: 01/27/2025] [Accepted: 01/29/2025] [Indexed: 02/05/2025] Open
Abstract
Tissue-resident lymphocytes play a crucial role in immune surveillance against cancer, yet their complex interactions and regulatory pathways remain underexplored, highlighting the need for a deeper understanding to enhance cancer immunotherapy strategies. Lymphocytes across the range of innate-adaptive responses can establish long-lasting presence in tissues, exerting a vital function in the local immune response against diverse antigens. These tissue-resident lymphocytes identify antigens and alarmins secreted by microbial infections and non-infectious stresses at barrier locations by closely interacting with epithelial and endothelial cells. Then they initiate effector responses to restore tissue homeostasis. Significantly, this immune defense system has been demonstrated to monitor the processes of epithelial cell transformation, carcinoma advancement, and cancer metastasis at remote locations, so establishing it as an essential element of cancer immunological surveillance. This review aims to elucidate the roles of diverse tissue-resident lymphocyte populations in shaping cancer immune responses and to investigate their synergistic effector mechanisms for advancing cancer immunotherapy.
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Affiliation(s)
- Ashiq Ali
- Department of Histology and Embryology, Shantou University Medical College, Shantou, China.
| | - Khadija Younas
- Department of Theriogenology, University of Agriculture, Faisalabad, Pakistan
| | - Aisha Khatoon
- Department of Pathology, University of Agriculture, Faisalabad, Pakistan
| | - Bilal Murtaza
- Dalian University of Science and Technology, Dalian, China
| | - Ziyi Ji
- Department of Histology and Embryology, Shantou University Medical College, Shantou, China
| | - Kaynaat Akbar
- Department of Zoology, Wildlife and Fisheries, Faculty of Sciences, University of Agriculture, Faisalabad, Pakistan
| | - Qaisar Tanveer
- The Roslin Institute, The Royal (Dick) School of Veterinary Studies, The University of Edinburgh, EH25 9RG, UK
| | - Sami Ullah Khan Bahadur
- College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Colins, CO 80523, USA
| | - Zhongjing Su
- Department of Histology and Embryology, Shantou University Medical College, Shantou, China.
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2
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Zhang T, Jing J, Liang Y, Luo J, Cheng D, Qin S, Jiang H. Resveratrol-stimulated macrophage exosomes delivering lncRNA Snhg6 inhibit liver fibrosis by modulating the NF-κB pathway. Genomics 2025; 117:111043. [PMID: 40147729 DOI: 10.1016/j.ygeno.2025.111043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Revised: 03/02/2025] [Accepted: 03/23/2025] [Indexed: 03/29/2025]
Abstract
OBJECTIVE To investigate the role of lncRNA Snhg6 in liver fibrosis, delivered by resveratrol-stimulated macrophage exosomes. METHODS Resveratrol-stimulated and unstimulated exosomes were generated from RAW 264.7 cells, confirmed by electron microscopy, nanoparticle analysis, and Western blotting. JS1 cells were used as an HSC model, activated with TGF-β1 and treated with exosomes. Exosome uptake was observed via confocal microscopy, and acta2 expression was measured with immunofluorescence. RNA sequencing and RT-qPCR were used to analyze exosomal lncRNA profiles. KEGG GSEA enrichment was conducted on differentially expressed genes, and nf-κb expression was detected in HSCs using WB. Serum from liver fibrosis patients was analyzed for SNHG6 levels. RESULTS Resveratrol-stimulated exosomes inhibited TGF-β1-induced HSC activation, with 132 differentially expressed lncRNAs, including upregulated Snhg6. NF-κB signaling was downregulated. Silencing Snhg6 weakened this inhibitory effect. CONCLUSION Resveratrol-stimulated macrophage exosomes may inhibit liver fibrosis by delivering lncRNA Snhg6, which suppresses the NF-κB pathway.
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Affiliation(s)
- Taicheng Zhang
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, No. 6, Shuangyong Road, Nanning 530021, Guangxi, China
| | - Jie Jing
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, No. 6, Shuangyong Road, Nanning 530021, Guangxi, China
| | - Yaodan Liang
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, No. 6, Shuangyong Road, Nanning 530021, Guangxi, China
| | - Jianming Luo
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, No. 6, Shuangyong Road, Nanning 530021, Guangxi, China
| | - Dongyu Cheng
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, No. 6, Shuangyong Road, Nanning 530021, Guangxi, China
| | - Shanyu Qin
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, No. 6, Shuangyong Road, Nanning 530021, Guangxi, China.
| | - Haixing Jiang
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, No. 6, Shuangyong Road, Nanning 530021, Guangxi, China.
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3
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Zhan C, Peng C, Wei H, Wei K, Ou Y, Zhang Z. Diverse Subsets of γδT Cells and Their Specific Functions Across Liver Diseases. Int J Mol Sci 2025; 26:2778. [PMID: 40141420 PMCID: PMC11943347 DOI: 10.3390/ijms26062778] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2025] [Revised: 03/15/2025] [Accepted: 03/17/2025] [Indexed: 03/28/2025] Open
Abstract
γδT cells, a distinct group of T lymphocytes, serve as a link between innate and adaptive immune responses. They are pivotal in the pathogenesis of various liver disorders, such as viral hepatitis, nonalcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), liver fibrosis, autoimmune liver diseases, and hepatocellular carcinoma (HCC). Despite their importance, the functional diversity and regulatory mechanisms of γδT cells remain incompletely understood. Recent advances in high-throughput single-cell sequencing and spatial transcriptomics have revealed significant heterogeneity among γδT cell subsets, particularly Vδ1+ and Vδ2+, which exhibit distinct immunological roles. Vδ1+ T cells are mainly tissue-resident and contribute to tumor immunity and chronic inflammation, while Vδ2+ T cells, predominantly found in peripheral blood, play roles in systemic immune surveillance but may undergo dysfunction in chronic liver diseases. Additionally, γδT17 cells exacerbate inflammation in NAFLD and ALD, whereas IFN-γ-secreting γδT cells contribute to antiviral and antifibrotic responses. These discoveries have laid the foundation for the creation of innovative solutions. γδT cell-based immunotherapeutic approaches, such as adoptive cell transfer, immune checkpoint inhibition, and strategies targeting metabolic pathways. Future research should focus on harnessing γδT cells' therapeutic potential through targeted interventions, offering promising prospects for precision immunotherapy in liver diseases.
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Affiliation(s)
- Chenjie Zhan
- State Key Laboratory of Targeting Oncology, National Center for International Research of Bio-Targeting Theranostics, Guangxi Key Laboratory of Bio-Targeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Talent Highland of Major New Drugs Innovation and Development, Guangxi Medical University, Nanning 530021, China; (C.Z.); (C.P.)
| | - Chunxiu Peng
- State Key Laboratory of Targeting Oncology, National Center for International Research of Bio-Targeting Theranostics, Guangxi Key Laboratory of Bio-Targeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Talent Highland of Major New Drugs Innovation and Development, Guangxi Medical University, Nanning 530021, China; (C.Z.); (C.P.)
| | - Huaxiu Wei
- State Key Laboratory of Targeting Oncology, National Center for International Research of Bio-Targeting Theranostics, Guangxi Key Laboratory of Bio-Targeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Talent Highland of Major New Drugs Innovation and Development, Guangxi Medical University, Nanning 530021, China; (C.Z.); (C.P.)
| | - Ke Wei
- State Key Laboratory of Targeting Oncology, National Center for International Research of Bio-Targeting Theranostics, Guangxi Key Laboratory of Bio-Targeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Talent Highland of Major New Drugs Innovation and Development, Guangxi Medical University, Nanning 530021, China; (C.Z.); (C.P.)
| | - Yangzhi Ou
- State Key Laboratory of Targeting Oncology, National Center for International Research of Bio-Targeting Theranostics, Guangxi Key Laboratory of Bio-Targeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Talent Highland of Major New Drugs Innovation and Development, Guangxi Medical University, Nanning 530021, China; (C.Z.); (C.P.)
| | - Zhiyong Zhang
- State Key Laboratory of Targeting Oncology, National Center for International Research of Bio-Targeting Theranostics, Guangxi Key Laboratory of Bio-Targeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Talent Highland of Major New Drugs Innovation and Development, Guangxi Medical University, Nanning 530021, China; (C.Z.); (C.P.)
- Department of Surgery, Robert-Wood-Johnson Medical School University Hospital, Rutgers University, New Brunswick, NJ 08901-8554, USA
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Pan Z, Ye YS, Liu C, Li W. Role of liver-resident NK cells in liver immunity. Hepatol Int 2025:10.1007/s12072-025-10778-7. [PMID: 39893278 DOI: 10.1007/s12072-025-10778-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2024] [Accepted: 01/10/2025] [Indexed: 02/04/2025]
Abstract
The tolerogenic immune microenvironment of the liver (the immune system avoids attacking harmless antigens, such as antigens derived from food and gut microbiota) has garnered significant attention in recent years. Inherent immune cells in the liver play a unique role in regulating this microenvironment. Liver-resident natural killer (LrNK) cells, also known as liver type 1 innate lymphoid cells (ILC1s), are a recently discovered subset of immune cells that possess properties distinct from those of conventional NK (cNK) cells. Accumulating evidence suggests that there are significant differences between LrNK and cNK cells, with LrNK cells potentially exhibiting immunosuppressive functions in the liver. This review summarizes the latest findings on LrNK cells, focusing on their phenotype, heterogeneity, plasticity, origin, development, and the required transcription factors. In addition, immune functions of LrNK cells in various liver diseases, including liver cancer, viral infections, liver injury, and cirrhosis, were analyzed. By elucidating the role of LrNK cells in liver immunity, this review aims to enhance our understanding of the mechanisms underlying liver immunity and contribute to the improvement of liver disease treatment.
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Affiliation(s)
- Zheng Pan
- Department of Hepatobiliary-Pancreatic Surgery, China-Japan Union Hospital of Jilin University, Changchun, 130033, China
| | - Yan-Shuo Ye
- Department of Hepatobiliary-Pancreatic Surgery, China-Japan Union Hospital of Jilin University, Changchun, 130033, China
| | - Chang Liu
- Department of Hepatobiliary-Pancreatic Surgery, China-Japan Union Hospital of Jilin University, Changchun, 130033, China
| | - Wei Li
- Department of Hepatobiliary-Pancreatic Surgery, China-Japan Union Hospital of Jilin University, Changchun, 130033, China.
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Huang Y, Liao H, Luo J, Wei H, Li A, Lu Y, Xiang B. Reversing NK cell exhaustion: a novel strategy combining immune checkpoint blockade with drug sensitivity enhancement in the treatment of hepatocellular carcinoma. Front Oncol 2025; 14:1502270. [PMID: 39906665 PMCID: PMC11790413 DOI: 10.3389/fonc.2024.1502270] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2024] [Accepted: 12/20/2024] [Indexed: 02/06/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common lethal cancers worldwide. Natural killer cells (NK cells) play a key role in liver immunosurveillance, but in the tumor microenvironment, NK cells are readily depleted, as evidenced by down-regulation of activating receptors, reduced cytokine secretion, and attenuated killing function. The up-regulation of inhibitory receptors, such as PD-1, TIM-3, and LAG-3, further exacerbates the depletion of NK cells. Combined blockade strategies targeting these immunosuppressive mechanisms, such as the combination of PD-1 inhibitors with other inhibitory pathways (eg. TIM-3 and LAG-3), have shown potential to reverse NK cell exhaustion in preclinical studies. This article explores the promise of these innovative strategies in HCC immunotherapy, providing new therapeutic directions for optimizing NK cell function and improving drug sensitivity.
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Affiliation(s)
| | | | | | | | | | | | - Bangde Xiang
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, China
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6
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Heuser SK, Li J, Pudewell S, LoBue A, Li Z, Cortese-Krott MM. Biochemistry, pharmacology, and in vivo function of arginases. Pharmacol Rev 2025; 77:100015. [PMID: 39952693 DOI: 10.1124/pharmrev.124.001271] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2024] [Revised: 09/24/2024] [Accepted: 10/07/2024] [Indexed: 01/22/2025] Open
Abstract
The enzyme arginase catalyzes the hydrolysis of l-arginine into l-ornithine and urea. The 2 existing isoforms Arg1 and Arg2 exhibit different cellular localizations and metabolic functions. Arginase activity is crucial for nitrogen detoxification in the urea cycle, synthesis of polyamines, and control of l-arginine bioavailability and nitric oxide (NO) production. Despite significant progress in the understanding of the biochemistry and function of arginases, several open questions remain. Recent studies have revealed that the regulation and function of Arg1 and Arg2 are cell type-specific, species-specific, and profoundly different in mice and humans. The main differences are in the distribution and function of Arg1 and Arg2 in immune and erythroid cells. Contrary to what was previously thought, Arg1 activity appears to be only partially related to vascular NO signaling under homeostatic conditions in the vascular wall, but its expression is increased under disease conditions and may be targeted by treatment with arginase inhibitors. Arg2 appears to be mainly a catabolic enzyme involved in the synthesis of l-ornithine, polyamine, and l-proline but may play a putative role in blood pressure control, at least in mice. The immunosuppressive role of arginase-mediated arginine depletion is a promising target for cancer treatment. This review critically revises and discusses the biochemistry, pharmacology, and in vivo function of arginases, focusing on the insights gained from the analysis of cell-specific Arg1 and Arg2 knockout mice and human studies using arginase inhibitors or pegylated recombinant arginase. SIGNIFICANCE STATEMENT: Further basic and translational research is needed to deepen our understanding of the regulation of Arg1 and Arg2 in different cell types in consideration of their localization, species-specificity, and multiple biochemical and physiological roles. This will lead to better pharmacological strategies to target arginase activity in liver, cardiovascular, hematological, immune/infectious diseases, and cancer.
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Affiliation(s)
- Sophia K Heuser
- Myocardial Infarction Research Laboratory, Department of Cardiology, Pulmonology, and Angiology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
| | - Junjie Li
- Myocardial Infarction Research Laboratory, Department of Cardiology, Pulmonology, and Angiology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
| | - Silke Pudewell
- Department of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
| | - Anthea LoBue
- Myocardial Infarction Research Laboratory, Department of Cardiology, Pulmonology, and Angiology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
| | - Zhixin Li
- Myocardial Infarction Research Laboratory, Department of Cardiology, Pulmonology, and Angiology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
| | - Miriam M Cortese-Krott
- Myocardial Infarction Research Laboratory, Department of Cardiology, Pulmonology, and Angiology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany; Cardiovascular Research Institute Düsseldorf, Düsseldorf, Germany; Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
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7
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Yang X, Li J, Ren M, Pan X, Liu H, Jiang J, Li M, Yang Z, Han B, Ma L, Hao J, Duan Y, Yin Z, Xu Y, Xiang Z, Wu B. Comprehensive analysis of immune signatures in primary biliary cholangitis and autoimmune hepatitis. J Leukoc Biol 2024; 117:qiae085. [PMID: 38652703 DOI: 10.1093/jleuko/qiae085] [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: 01/07/2024] [Revised: 03/14/2024] [Accepted: 03/20/2024] [Indexed: 04/25/2024] Open
Abstract
Primary biliary cholangitis (PBC) and autoimmune hepatitis (AIH) are autoimmune diseases that target hepatocytes and bile duct cells, respectively. Despite their shared autoimmune nature, the differences in immunologic characteristics between them remain largely unexplored. This study seeks to elucidate the unique immunological profiles of PBC and AIH and to identify key differences. We comprehensively analyzed various T cell subsets and their receptor expression in a cohort of 45 patients, including 27 PBC and 18 AIH cases. Both diseases exhibited T cell exhaustion and senescence along with a surge in inflammatory cytokines. Significantly increased CD38+HLA-DR+CD8+ T cell populations were observed in both diseases. AIH was characterized by an upregulation of CD8+ terminally differentiated T, CD4+ effector memory T, and CD4+ terminally differentiated T cells, and a concurrent reduction in regulatory T cells. In contrast, PBC displayed a pronounced presence of T follicular helper (Tfh) cells and a contraction of CD4-CD8- T cell populations. Correlation analysis revealed that NKP46+ natural killer frequency was closely tied to alanine aminotransferase and aspartate aminotransferase levels, and TIGIT expression on T cells was associated with globulin level in AIH. In PBC, there is a significant correlation between Tfh cells and ALP levels. Moreover, the identified immune landscapes in both diseases strongly related to disease severity. Through logistic regression analysis, γδ T, TIGIT+Vδ2 T, and Tfh1 cell frequencies emerged as distinct markers capable of differentiating PBC from AIH. In conclusion, our analyses reveal that PBC and AIH share similarities and differences regarding to immune profiles. γδ T, TIGIT+Vδ2 T, and Tfh1 cell frequencies are potential noninvasive immunological markers that can differentiate PBC from AIH.
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Affiliation(s)
- Xiaoxue Yang
- Department of Gastroenterology, Third Affiliated Hospital of Sun Yat-Sen University, No. 600 Tianhe Road, Tianhe District, Guangzhou, Guangdong 510630, China
| | - Jiawei Li
- The Biomedical Translational Research Institute, Health Science Center (School of Medicine), Jinan University, No. 601 Huangpu W.Road, Tianhe District, Guangzhou, Guangdong 510632, China
- Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai People's Hospital Affiliated with Jinan University, Jinan University, No. 79 Kangning Road, Xiangzhou District, Zhuhai, Guangdong 519000, China
| | - Meiling Ren
- Yuexiu District Center for Disease Control and Prevention, No. 23, Jiaochang West Road, Yuexiu District, Guangzhou, Guangdong 510120, China
| | - Xuemei Pan
- Department of Gastroenterology, Third Affiliated Hospital of Sun Yat-Sen University, No. 600 Tianhe Road, Tianhe District, Guangzhou, Guangdong 510630, China
| | - Huiling Liu
- Department of Gastroenterology, Third Affiliated Hospital of Sun Yat-Sen University, No. 600 Tianhe Road, Tianhe District, Guangzhou, Guangdong 510630, China
| | - Jie Jiang
- Department of Gastroenterology, Third Affiliated Hospital of Sun Yat-Sen University, No. 600 Tianhe Road, Tianhe District, Guangzhou, Guangdong 510630, China
| | - Man Li
- The Biomedical Translational Research Institute, Health Science Center (School of Medicine), Jinan University, No. 601 Huangpu W.Road, Tianhe District, Guangzhou, Guangdong 510632, China
- Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai People's Hospital Affiliated with Jinan University, Jinan University, No. 79 Kangning Road, Xiangzhou District, Zhuhai, Guangdong 519000, China
| | - Zhe Yang
- The Biomedical Translational Research Institute, Health Science Center (School of Medicine), Jinan University, No. 601 Huangpu W.Road, Tianhe District, Guangzhou, Guangdong 510632, China
- Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai People's Hospital Affiliated with Jinan University, Jinan University, No. 79 Kangning Road, Xiangzhou District, Zhuhai, Guangdong 519000, China
| | - Bingyu Han
- The Biomedical Translational Research Institute, Health Science Center (School of Medicine), Jinan University, No. 601 Huangpu W.Road, Tianhe District, Guangzhou, Guangdong 510632, China
- Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai People's Hospital Affiliated with Jinan University, Jinan University, No. 79 Kangning Road, Xiangzhou District, Zhuhai, Guangdong 519000, China
| | - Lina Ma
- The Biomedical Translational Research Institute, Health Science Center (School of Medicine), Jinan University, No. 601 Huangpu W.Road, Tianhe District, Guangzhou, Guangdong 510632, China
- Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai People's Hospital Affiliated with Jinan University, Jinan University, No. 79 Kangning Road, Xiangzhou District, Zhuhai, Guangdong 519000, China
| | - Jianlei Hao
- The Biomedical Translational Research Institute, Health Science Center (School of Medicine), Jinan University, No. 601 Huangpu W.Road, Tianhe District, Guangzhou, Guangdong 510632, China
- Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai People's Hospital Affiliated with Jinan University, Jinan University, No. 79 Kangning Road, Xiangzhou District, Zhuhai, Guangdong 519000, China
| | - Yuanyuan Duan
- Department of Microbiology and Immunology, Health Science Center, School of Medicine, Jinan University, No. 601 Huangpu W.Road, Tianhe District, Guangzhou, Guangdong 510632, China
- Key Laboratory of Viral Pathogenesis and Infection Prevention and Control, Jinan University, Ministry of Education, No. 601 Huangpu W.Road, Tianhe District, Guangzhou, Guangdong 510632, China
| | - Zhinan Yin
- The Biomedical Translational Research Institute, Health Science Center (School of Medicine), Jinan University, No. 601 Huangpu W.Road, Tianhe District, Guangzhou, Guangdong 510632, China
- Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai People's Hospital Affiliated with Jinan University, Jinan University, No. 79 Kangning Road, Xiangzhou District, Zhuhai, Guangdong 519000, China
| | - Yan Xu
- The Biomedical Translational Research Institute, Health Science Center (School of Medicine), Jinan University, No. 601 Huangpu W.Road, Tianhe District, Guangzhou, Guangdong 510632, China
- Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai People's Hospital Affiliated with Jinan University, Jinan University, No. 79 Kangning Road, Xiangzhou District, Zhuhai, Guangdong 519000, China
| | - Zheng Xiang
- Department of Microbiology and Immunology, Health Science Center, School of Medicine, Jinan University, No. 601 Huangpu W.Road, Tianhe District, Guangzhou, Guangdong 510632, China
- Key Laboratory of Viral Pathogenesis and Infection Prevention and Control, Jinan University, Ministry of Education, No. 601 Huangpu W.Road, Tianhe District, Guangzhou, Guangdong 510632, China
| | - Bin Wu
- Department of Gastroenterology, Third Affiliated Hospital of Sun Yat-Sen University, No. 600 Tianhe Road, Tianhe District, Guangzhou, Guangdong 510630, China
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8
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Kojima H, Morinelli TA, Wang Y, Chin JL, Meyer AS, Kao YC, Kadono K, Yao S, Torgerson T, Dery KJ, Bhat A, Reed EF, Kaldas FM, van der Windt DJ, Farmer DG, Kupiec-Weglinski JW, Zhai Y. Group 1 innate lymphoid cells protect liver transplants from ischemia-reperfusion injury via an interferon gamma-mediated pathway. Am J Transplant 2024:S1600-6135(24)00793-7. [PMID: 39736469 DOI: 10.1016/j.ajt.2024.11.035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Revised: 11/07/2024] [Accepted: 11/23/2024] [Indexed: 01/01/2025]
Abstract
As important immune regulatory cells, whether innate lymphoid cells (ILCs) are involved in liver transplantation (LT) remains unclear. In a murine orthotopic LT model, we dissected roles of ILCs in liver ischemia-reperfusion injury (IRI). Wild-type (WT) grafts suffered significantly higher IRI in Rag2-γc double knockout (DKO) than Rag2 knockout (KO) recipients, in association with downregulation of group 1 ILCs genes, including interferon gamma. Antibody-mediated ILC depletion or interferon gamma neutralization in Rag2 KO recipients increased, while interferon gamma treatment in DKO recipients reduced, liver graft injuries. At the donor side, grafts from DKO mice or anti-NK1.1-treated WT mice suffered significantly higher IRI, while grafts treated with interferon gamma during cold preservation decreased IRI. Thus, both recipient and donor group 1 ILCs protect liver grafts from IRI. Low-dose interferon gamma upregulated c-FLIP expression in vitro and in vivo and protected hepatocytes from inflammatory cell death. In human liver graft biopsies, single-cell RNA-sequencing analysis revealed group 1 ILCs produce interferon gamma. The c-FLIP levels were positively correlated with interferon gamma in pretransplant biopsies. Grafts with higher c-FLIP were associated with lower caspase-8 activation, IRI gradings, and frequency of early allograft dysfunction post-LT. Our study reveals a novel interferon gamma-mediated cytoprotective role of group 1 ILCs in LT.
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Affiliation(s)
- Hidenobu Kojima
- The Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Thomas A Morinelli
- Department of Surgery, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Yue Wang
- Department of Surgery, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Jackson L Chin
- Department of Bioengineering, University of California, Los Angeles, Los Angeles, California, USA
| | - Aaron S Meyer
- Department of Bioengineering, University of California, Los Angeles, Los Angeles, California, USA
| | - Yi-Chu Kao
- Department of Surgery, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Kentaro Kadono
- The Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Siyuan Yao
- The Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Taylor Torgerson
- The Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Kenneth J Dery
- The Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Adil Bhat
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Elaine F Reed
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Fady M Kaldas
- The Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Dirk J van der Windt
- Department of Surgery, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Douglas G Farmer
- The Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Jerzy W Kupiec-Weglinski
- The Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Yuan Zhai
- The Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at UCLA, Los Angeles, California, USA; Department of Surgery, Medical University of South Carolina, Charleston, South Carolina, USA.
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Nguyen HH, Talbot J, Li D, Raghavan V, Littman DR. Modulating intestinal neuroimmune VIPergic signaling attenuates the reduction in ILC3-derived IL-22 and hepatic steatosis in MASLD. Hepatol Commun 2024; 8:e0528. [PMID: 39761015 PMCID: PMC11495769 DOI: 10.1097/hc9.0000000000000528] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2024] [Accepted: 07/18/2024] [Indexed: 01/07/2025] Open
Abstract
BACKGROUND Metabolic dysfunction-associated steatotic liver disease (MASLD, formerly known as NAFLD) is a major driver of cirrhosis and liver-related mortality. However, therapeutic options for MASLD, including prevention of liver steatosis, are limited. We previously described that vasoactive intestinal peptide-producing neurons (VIP-neurons) regulate the efficiency of intestinal dietary fat absorption and IL-22 production by type 3 innate lymphoid cells (ILC3) in the intestine. Given the described hepatoprotective role of IL-22, we hypothesize that modulation of this neuroimmune circuit could potentially be an innovative approach for the control of liver steatosis. METHODS We used a model of diet-induced MASLD by exposing mice to a high-fat diet (HFD) for 16 weeks, when the development of liver steatosis was first observed in our animals. We characterized IL-22 production by intestinal ILC3 at this dietary endpoint. We then evaluated whether communication between VIP-neurons and ILC3 affected IL-22 production and MASLD development by exposing mice with a conditional genetic deletion of Vipr2 in ILC3 (Rorc(t)CreVipr2fl/fl) to the HFD. We also performed intermittent global inhibition of VIP-neurons using a chemogenetic inhibitory approach (VipIres-CrehM4DiLSL) in HFD-fed mice. RESULTS Production of IL-22 by intestinal ILC3 is reduced in steatotic mice that were exposed to an HFD for 16 weeks. Targeted deletion of VIP receptor 2 in ILC3 resulted in higher production of IL-22 in ILC3 and was associated with a significant reduction in liver steatosis in mice under HFD. Global inhibition of VIP-producing neurons also resulted in a significant reduction in liver steatosis. CONCLUSIONS Modulating VIPergic neuroimmune signaling can ameliorate the development of hepatic steatosis induced by a surplus of fat ingestion in the diet. This neuroimmune pathway should be further investigated as a potential therapeutic avenue in MASLD.
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Affiliation(s)
- Henry H. Nguyen
- Department of Cell Biology, New York University School of Medicine, New York, New York, USA
- Department of Medicine and Department of Microbiology, Immunology, and Infectious Diseases, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Jhimmy Talbot
- Department of Cell Biology, New York University School of Medicine, New York, New York, USA
- Basic Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Dayi Li
- Department of Cell Biology, New York University School of Medicine, New York, New York, USA
| | - Varsha Raghavan
- Department of Cell Biology, New York University School of Medicine, New York, New York, USA
| | - Dan R. Littman
- Department of Cell Biology, New York University School of Medicine, New York, New York, USA
- Howard Hughes Medical Institute, New York, New York, USA
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Zhang WH, Zhao Y, Zhang CR, Huang JC, Lyu SC, Lang R. Preoperative systemic inflammatory response index as a prognostic marker for distal cholangiocarcinoma after pancreatoduodenectomy. World J Gastrointest Surg 2024; 16:2910-2924. [PMID: 39351557 PMCID: PMC11438816 DOI: 10.4240/wjgs.v16.i9.2910] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Revised: 08/05/2024] [Accepted: 08/13/2024] [Indexed: 09/18/2024] Open
Abstract
BACKGROUND The relationship between preoperative inflammation status and tumorigenesis as well as tumor progression is widely acknowledged. AIM To assess the prognostic significance of preoperative inflammatory biomarkers in patients with distal cholangiocarcinoma (dCCA) who underwent pancreatoduodenectomy (PD). METHODS This single-center study included 216 patients with dCCA after PD between January 1, 2011, and December 31, 2022. The individuals were categorized into two sets based on their systemic inflammatory response index (SIRI) levels: A low SIRI group (SIRI < 1.5, n = 123) and a high SIRI group (SIRI ≥ 1.5, n = 93). Inflammatory biomarkers were evaluated for predictive accuracy using receiver operating characteristic curves. Both univariate and multivariate Cox proportional hazards analyses were performed to estimate SIRI for overall survival (OS) and recurrence-free survival (RFS). RESULTS The study included a total of 216 patients, with 58.3% being male and a mean age of 65.6 ± 9.6 years. 123 patients were in the low SIRI group and 93 were in the high SIRI group after PD for dCCA. SIRI had an area under the curve value of 0.674 for diagnosing dCCA, showing better performance than other inflammatory biomarkers. Multivariate analysis indicated that having a SIRI greater than 1.5 independently increased the risk of dCCA following PD, leading to lower OS [hazard ratios (HR) = 1.868, P = 0.006] and RFS (HR = 0.949, P < 0.001). Additionally, survival analysis indicated a significantly better prognosis for patients in the low SIRI group (P < 0.001). CONCLUSION It is determined that a high SIRI before surgery is a significant risk factor for dCCA after PD.
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Affiliation(s)
- Wen-Hui Zhang
- Department of Hepatobiliary Surgery, Beijing Chao-Yang Hospital Affiliated to Capital Medical University, Beijing 100020, China
| | - Yu Zhao
- Department of Urology Surgery, Beijing Chao-Yang Hospital Affiliated to Capital Medical University, Beijing 100020, China
| | - Cheng-Run Zhang
- Department of Hepatobiliary Surgery, Beijing Chao-Yang Hospital Affiliated to Capital Medical University, Beijing 100020, China
| | - Jin-Can Huang
- Department of Hepatobiliary Surgery, Beijing Chao-Yang Hospital Affiliated to Capital Medical University, Beijing 100020, China
| | - Shao-Cheng Lyu
- Department of Hepatobiliary Surgery, Beijing Chao-Yang Hospital Affiliated to Capital Medical University, Beijing 100020, China
| | - Ren Lang
- Department of Hepatobiliary Surgery, Beijing Chao-Yang Hospital Affiliated to Capital Medical University, Beijing 100020, China
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Morel D, Robert C, Paragios N, Grégoire V, Deutsch E. Translational Frontiers and Clinical Opportunities of Immunologically Fitted Radiotherapy. Clin Cancer Res 2024; 30:2317-2332. [PMID: 38477824 PMCID: PMC11145173 DOI: 10.1158/1078-0432.ccr-23-3632] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Revised: 01/09/2024] [Accepted: 02/13/2024] [Indexed: 03/14/2024]
Abstract
Ionizing radiation can have a wide range of impacts on tumor-immune interactions, which are being studied with the greatest interest and at an accelerating pace by the medical community. Despite its undeniable immunostimulatory potential, it clearly appears that radiotherapy as it is prescribed and delivered nowadays often alters the host's immunity toward a suboptimal state. This may impair the full recovery of a sustained and efficient antitumor immunosurveillance posttreatment. An emerging concept is arising from this awareness and consists of reconsidering the way of designing radiation treatment planning, notably by taking into account the individualized risks of deleterious radio-induced immune alteration that can be deciphered from the planned beam trajectory through lymphocyte-rich organs. In this review, we critically appraise key aspects to consider while planning immunologically fitted radiotherapy, including the challenges linked to the identification of new dose constraints to immune-rich structures. We also discuss how pharmacologic immunomodulation could be advantageously used in combination with radiotherapy to compensate for the radio-induced loss, for example, with (i) agonists of interleukin (IL)2, IL4, IL7, IL9, IL15, or IL21, similarly to G-CSF being used for the prophylaxis of severe chemo-induced neutropenia, or with (ii) myeloid-derived suppressive cell blockers.
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Affiliation(s)
- Daphné Morel
- Department of Radiation Oncology, Gustave Roussy, Villejuif, France
- INSERM U1030, Molecular Radiotherapy, Villejuif, France
| | - Charlotte Robert
- Department of Radiation Oncology, Gustave Roussy, Villejuif, France
- INSERM U1030, Molecular Radiotherapy, Villejuif, France
- Paris-Saclay University, School of Medicine, Le Kremlin Bicêtre, France
| | - Nikos Paragios
- Therapanacea, Paris, France
- CentraleSupélec, Gif-sur-Yvette, France
| | - Vincent Grégoire
- Department of Radiation Oncology, Centre Léon Bérard, Lyon, France
| | - Eric Deutsch
- Department of Radiation Oncology, Gustave Roussy, Villejuif, France
- INSERM U1030, Molecular Radiotherapy, Villejuif, France
- Paris-Saclay University, School of Medicine, Le Kremlin Bicêtre, France
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12
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Bitterer F, Kupke P, Adenugba A, Evert K, Glehr G, Riquelme P, Scheibert L, Preverin G, Böhm C, Hornung M, Schlitt HJ, Wenzel JJ, Geissler EK, Safinia N, Hutchinson JA, Werner JM. Soluble CD46 as a diagnostic marker of hepatic steatosis. EBioMedicine 2024; 104:105184. [PMID: 38838471 PMCID: PMC11179574 DOI: 10.1016/j.ebiom.2024.105184] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Revised: 05/21/2024] [Accepted: 05/21/2024] [Indexed: 06/07/2024] Open
Abstract
BACKGROUND The increasing prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) incurs substantial morbidity, mortality and healthcare costs. Detection and clinical intervention at early stages of disease improves prognosis; however, we are currently limited by a lack of reliable diagnostic tests for population screening and monitoring responses to therapy. To address this unmet need, we investigated human invariant Natural Killer T cell (iNKT) activation by fat-loaded hepatocytes, leading to the discovery that circulating soluble CD46 (sCD46) levels accurately predict hepatic steatosis. METHODS sCD46 in plasma was measured using a newly developed immuno-competition assay in two independent cohorts: Prospective living liver donors (n = 156; male = 66, female = 90) and patients with liver tumours (n = 91; male = 58, female = 33). sCD46 levels were statistically evaluated as a predictor of hepatic steatosis. FINDINGS Interleukin-4-secreting (IL-4+) iNKT cells were over-represented amongst intrahepatic lymphocytes isolated from resected human liver samples. IL-4+ iNKT cells preferentially developed in cocultures with a fat-loaded, hepatocyte-like cell line, HepaRG. This was attributed to induction of matrix metalloproteases (MMP) in fat-loaded HepaRG cells and primary human liver organoids, which led to indiscriminate cleavage of immune receptors. Loss of cell-surface CD46 resulted in unrepressed differentiation of IL-4+ iNKT cells. sCD46 levels were elevated in patients with hepatic steatosis. Discriminatory cut-off values for plasma sCD46 were found that accurately classified patients according to histological steatosis grade. INTERPRETATION sCD46 is a reliable clinical marker of hepatic steatosis, which can be conveniently and non-invasively measured in serum and plasma samples, raising the possibility of using sCD46 levels as a diagnostic method for detecting or grading hepatic steatosis. FUNDING F.B. was supported by the Else Kröner Foundation (Award 2016_kolleg.14). G.G. was supported by the Bristol Myers Squibb Foundation for Immuno-Oncology (Award FA-19-009). N.S. was supported by a Wellcome Trust Fellowship (211113/A/18/Z). J.A.H. received funding from the European Union's Horizon 2020 research and innovation programme (Award 860003). J.M.W. received funding from the Else Kröner Foundation (Award 2015_A10).
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Affiliation(s)
- Florian Bitterer
- Department of Surgery, University Hospital Regensburg, Regensburg 93053, Germany
| | - Paul Kupke
- Department of Surgery, University Hospital Regensburg, Regensburg 93053, Germany
| | - Akinbami Adenugba
- Department of Surgery, University Hospital Regensburg, Regensburg 93053, Germany
| | - Katja Evert
- Institute of Pathology, University of Regensburg, Regensburg 93053, Germany
| | - Gunther Glehr
- Department of Surgery, University Hospital Regensburg, Regensburg 93053, Germany
| | - Paloma Riquelme
- Department of Surgery, University Hospital Regensburg, Regensburg 93053, Germany
| | - Lena Scheibert
- Department of Surgery, University Hospital Regensburg, Regensburg 93053, Germany
| | - Giulia Preverin
- Department of Surgery, University Hospital Regensburg, Regensburg 93053, Germany
| | - Christina Böhm
- Oxford Nanopore Technologies PLC, Oxford Science Park, Oxford OX4 4DQ, United Kingdom
| | - Matthias Hornung
- Department of Surgery, University Hospital Regensburg, Regensburg 93053, Germany
| | - Hans J Schlitt
- Department of Surgery, University Hospital Regensburg, Regensburg 93053, Germany
| | - Jürgen J Wenzel
- Institute of Clinical Microbiology and Hygiene, University of Regensburg, Regensburg 93053, Germany
| | - Edward K Geissler
- Department of Surgery, University Hospital Regensburg, Regensburg 93053, Germany
| | - Niloufar Safinia
- Department of Hepatology, King's College London, London SE5 8AF, United Kingdom
| | - James A Hutchinson
- Department of Surgery, University Hospital Regensburg, Regensburg 93053, Germany.
| | - Jens M Werner
- Department of Surgery, University Hospital Regensburg, Regensburg 93053, Germany.
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Szafranska K, Sørensen KK, Lalor PF, McCourt P. Sinusoidal cells and liver immunology. SINUSOIDAL CELLS IN LIVER DISEASES 2024:53-75. [DOI: 10.1016/b978-0-323-95262-0.00003-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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Sun J, Zhao P, Shi Y, Li Y. Recent insight into the role of macrophage in alcohol-associated liver disease: a mini-review. Front Cell Dev Biol 2023; 11:1292016. [PMID: 38094617 PMCID: PMC10716218 DOI: 10.3389/fcell.2023.1292016] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2023] [Accepted: 11/20/2023] [Indexed: 03/05/2025] Open
Abstract
Alcohol-associated liver disease (ALD) is a condition that develops due to prolonged and excessive alcohol consumption. It encompasses various stages of liver damage, including fatty liver, alcoholic hepatitis, and cirrhosis. Immune cells, particularly macrophages, of various types play a significant role in the onset and progression of the disease. Macrophages observed in the liver exhibit diverse differentiation forms, and perform a range of functions. Beyond M1 and M2 macrophages, human macrophages can polarize into distinct phenotypes in response to various stimuli. Recent advancements have improved our understanding of macrophage diversity and their role in the progression of ALD. This mini-review provides a concise overview of the latest findings on the role and differentiation of macrophages in ALD. Additionally, it discusses potential therapeutic targets associated with macrophages and explores potential therapeutic strategies.
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Affiliation(s)
- Jialiang Sun
- Department of Pediatrics, The First Hospital of Jilin University, Changchun, China
| | - Peiliang Zhao
- Department of Pediatrics, The First Hospital of Jilin University, Changchun, China
| | - Ying Shi
- Department of Hepatology, The First Hospital of Jilin University, Changchun, China
| | - Yanan Li
- Department of Pediatrics, The First Hospital of Jilin University, Changchun, China
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15
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Zhong ZH, Liang L, Fu TW, Dai MG, Cheng J, Liu SY, Ye TW, Shen GL, Zhang CW, Huang DS, Liu JW. Prognostic value of platelet distribution width to lymphocyte ratio in patients with hepatocellular carcinoma following hepatectomy. BMC Cancer 2023; 23:1116. [PMID: 37974129 PMCID: PMC10655313 DOI: 10.1186/s12885-023-11621-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2023] [Accepted: 11/07/2023] [Indexed: 11/19/2023] Open
Abstract
BACKGROUND Platelet distribution width (PDW), but not platelet count, was found to more comprehensively reflect platelet activity. The present study, thus, aimed to evaluate the prognostic value of PDW to lymphocyte ratio (PDWLR) in patients with hepatocellular carcinoma (HCC) following hepatectomy. METHODS Patients following hepatectomy were analyzed retrospectively. The Kaplan-Meier survival curves and Cox regression model were used to determine the prognostic value of PDWLR. RESULTS 241 patients were analyzed eventually, and stratified into low and high PDWLR groups (≤ 9.66 vs. > 9.66). Results of comparing the baseline characteristics showed that high PDWLR was significantly associated with cirrhosis, and intraoperative blood loss (all P < 0.05). In multivariate COX regression analysis, PDWLR was demonstrated as an independent risk factor for OS (HR: 1.549, P = 0.041) and RFS (HR: 1.655, P = 0.005). Moreover, PDWLR demonstrated a superior capacity for predicting prognosis compared to other indicators. CONCLUSION Preoperative PDWLR has a potential value in predicting the prognosis of HCC patients following hepatectomy, which may help in clinical decision-making for individual treatment.
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Affiliation(s)
- Zhi-Han Zhong
- General Surgery, Cancer Center, Department of Hepatobiliary & Pancreatic Surgery and Minimally Invasive Surgery, Affiliated People's Hospital, Zhejiang Provincial People's Hospital, Hangzhou Medical College, Hangzhou, 310014, Zhejiang, China
| | - Lei Liang
- General Surgery, Cancer Center, Department of Hepatobiliary & Pancreatic Surgery and Minimally Invasive Surgery, Affiliated People's Hospital, Zhejiang Provincial People's Hospital, Hangzhou Medical College, Hangzhou, 310014, Zhejiang, China.
| | - Tian-Wei Fu
- General Surgery, Cancer Center, Department of Hepatobiliary & Pancreatic Surgery and Minimally Invasive Surgery, Affiliated People's Hospital, Zhejiang Provincial People's Hospital, Hangzhou Medical College, Hangzhou, 310014, Zhejiang, China
| | - Mu-Gen Dai
- Department of Gastroenterology, The Fifth Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China
| | - Jian Cheng
- General Surgery, Cancer Center, Department of Hepatobiliary & Pancreatic Surgery and Minimally Invasive Surgery, Affiliated People's Hospital, Zhejiang Provincial People's Hospital, Hangzhou Medical College, Hangzhou, 310014, Zhejiang, China
| | - Si-Yu Liu
- Department of Laboratory Medicine, The Key Laboratory of Imaging Diagnosis and Minimally Invasive Interventional Research of Zhejiang Province, Zhejiang University Lishui Hospital, Lishui, Zhejiang, China
| | - Tai-Wei Ye
- General Surgery, Cancer Center, Department of Hepatobiliary & Pancreatic Surgery and Minimally Invasive Surgery, Affiliated People's Hospital, Zhejiang Provincial People's Hospital, Hangzhou Medical College, Hangzhou, 310014, Zhejiang, China
- Department of the Second School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Guo-Liang Shen
- General Surgery, Cancer Center, Department of Hepatobiliary & Pancreatic Surgery and Minimally Invasive Surgery, Affiliated People's Hospital, Zhejiang Provincial People's Hospital, Hangzhou Medical College, Hangzhou, 310014, Zhejiang, China
| | - Cheng-Wu Zhang
- General Surgery, Cancer Center, Department of Hepatobiliary & Pancreatic Surgery and Minimally Invasive Surgery, Affiliated People's Hospital, Zhejiang Provincial People's Hospital, Hangzhou Medical College, Hangzhou, 310014, Zhejiang, China
| | - Dong-Sheng Huang
- General Surgery, Cancer Center, Department of Hepatobiliary & Pancreatic Surgery and Minimally Invasive Surgery, Affiliated People's Hospital, Zhejiang Provincial People's Hospital, Hangzhou Medical College, Hangzhou, 310014, Zhejiang, China
| | - Jun-Wei Liu
- General Surgery, Cancer Center, Department of Hepatobiliary & Pancreatic Surgery and Minimally Invasive Surgery, Affiliated People's Hospital, Zhejiang Provincial People's Hospital, Hangzhou Medical College, Hangzhou, 310014, Zhejiang, China.
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16
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Zhang Y, Fang XM. The pan-liver network theory: From traditional chinese medicine to western medicine. CHINESE J PHYSIOL 2023; 66:401-436. [PMID: 38149555 DOI: 10.4103/cjop.cjop-d-22-00131] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2023] Open
Abstract
In traditional Chinese medicine (TCM), the liver is the "general organ" that is responsible for governing/maintaining the free flow of qi over the entire body and storing blood. According to the classic five elements theory, zang-xiang theory, yin-yang theory, meridians and collaterals theory, and the five-viscera correlation theory, the liver has essential relationships with many extrahepatic organs or tissues, such as the mother-child relationships between the liver and the heart, and the yin-yang and exterior-interior relationships between the liver and the gallbladder. The influences of the liver to the extrahepatic organs or tissues have been well-established when treating the extrahepatic diseases from the perspective of modulating the liver by using the ancient classic prescriptions of TCM and the acupuncture and moxibustion. In modern medicine, as the largest solid organ in the human body, the liver has the typical functions of filtration and storage of blood; metabolism of carbohydrates, fats, proteins, hormones, and foreign chemicals; formation of bile; storage of vitamins and iron; and formation of coagulation factors. The liver also has essential endocrine function, and acts as an immunological organ due to containing the resident immune cells. In the perspective of modern human anatomy, physiology, and pathophysiology, the liver has the organ interactions with the extrahepatic organs or tissues, for example, the gut, pancreas, adipose, skeletal muscle, heart, lung, kidney, brain, spleen, eyes, skin, bone, and sexual organs, through the circulation (including hemodynamics, redox signals, hepatokines, metabolites, and the translocation of microbiota or its products, such as endotoxins), the neural signals, or other forms of pathogenic factors, under normal or diseases status. The organ interactions centered on the liver not only influence the homeostasis of these indicated organs or tissues, but also contribute to the pathogenesis of cardiometabolic diseases (including obesity, type 2 diabetes mellitus, metabolic [dysfunction]-associated fatty liver diseases, and cardio-cerebrovascular diseases), pulmonary diseases, hyperuricemia and gout, chronic kidney disease, and male and female sexual dysfunction. Therefore, based on TCM and modern medicine, the liver has the bidirectional interaction with the extrahepatic organ or tissue, and this established bidirectional interaction system may further interact with another one or more extrahepatic organs/tissues, thus depicting a complex "pan-hepatic network" model. The pan-hepatic network acts as one of the essential mechanisms of homeostasis and the pathogenesis of diseases.
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Affiliation(s)
- Yaxing Zhang
- Department of Physiology; Research Centre of Basic Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong; Issue 12th of Guangxi Apprenticeship Education of Traditional Chinese Medicine (Shi-Cheng Class of Guangxi University of Chinese Medicine), College of Continuing Education, Guangxi University of Chinese Medicine, Nanning, Guangxi, China
| | - Xian-Ming Fang
- Department of Cardiology, Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine (Guangxi Hospital of Integrated Chinese Medicine and Western Medicine, Ruikang Clinical Faculty of Guangxi University of Chinese Medicine), Guangxi University of Chinese Medicine, Nanning, Guangxi, China
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Duan M, Liu X, Yang Y, Zhang Y, Wu R, Lv Y, Lei H. Orchestrated regulation of immune inflammation with cell therapy in pediatric acute liver injury. Front Immunol 2023; 14:1194588. [PMID: 37426664 PMCID: PMC10323196 DOI: 10.3389/fimmu.2023.1194588] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Accepted: 05/26/2023] [Indexed: 07/11/2023] Open
Abstract
Acute liver injury (ALI) in children, which commonly leads to acute liver failure (ALF) with the need for liver transplantation, is a devastating life-threatening condition. As the orchestrated regulation of immune hemostasis in the liver is essential for resolving excess inflammation and promoting liver repair in a timely manner, in this study we focused on the immune inflammation and regulation with the functional involvement of both innate and adaptive immune cells in acute liver injury progression. In the context of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic, it was also important to incorporate insights from the immunological perspective for the hepatic involvement with SARS-CoV-2 infection, as well as the acute severe hepatitis of unknown origin in children since it was first reported in March 2022. Furthermore, molecular crosstalk between immune cells concerning the roles of damage-associated molecular patterns (DAMPs) in triggering immune responses through different signaling pathways plays an essential role in the process of liver injury. In addition, we also focused on DAMPs such as high mobility group box 1 (HMGB1) and cold-inducible RNA-binding protein (CIRP), as well as on macrophage mitochondrial DNA-cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway in liver injury. Our review also highlighted novel therapeutic approaches targeting molecular and cellular crosstalk and cell-based therapy, providing a future outlook for the treatment of acute liver injury.
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Affiliation(s)
- Mingyue Duan
- Department of Clinical Laboratory, The Affiliated Children’s Hospital of Xi’an Jiaotong University, Xi’an, China
- Key Laboratory of Precision Medicine to Pediatric Diseases of Shaanxi Province, Shaanxi Institute for Pediatric Diseases, The Affiliated Children’s Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Xiaoguai Liu
- Department of Infectious Diseases, The Affiliated Children’s Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Ying Yang
- Key Laboratory of Precision Medicine to Pediatric Diseases of Shaanxi Province, Shaanxi Institute for Pediatric Diseases, The Affiliated Children’s Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Yanmin Zhang
- Key Laboratory of Precision Medicine to Pediatric Diseases of Shaanxi Province, Shaanxi Institute for Pediatric Diseases, The Affiliated Children’s Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Rongqian Wu
- National Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Yi Lv
- National Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Hong Lei
- Key Laboratory of Precision Medicine to Pediatric Diseases of Shaanxi Province, Shaanxi Institute for Pediatric Diseases, The Affiliated Children’s Hospital of Xi’an Jiaotong University, Xi’an, China
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18
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Greten TF, Schwabe R, Bardeesy N, Ma L, Goyal L, Kelley RK, Wang XW. Immunology and immunotherapy of cholangiocarcinoma. Nat Rev Gastroenterol Hepatol 2023; 20:349-365. [PMID: 36697706 DOI: 10.1038/s41575-022-00741-4] [Citation(s) in RCA: 72] [Impact Index Per Article: 36.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/23/2022] [Indexed: 01/27/2023]
Abstract
Cholangiocarcinoma is the second most common primary liver cancer. Its incidence is low in the Western world but is rising globally. Surgery, chemotherapy and radiation therapy have been the only treatment options for decades. Progress in our molecular understanding of the disease and the identification of druggable targets, such as IDH1 mutations and FGFR2 fusions, has provided new treatment options. Immunotherapy has emerged as a potent strategy for many different types of cancer and has shown efficacy in combination with chemotherapy for cholangiocarcinoma. In this Review, we discuss findings related to key immunological aspects of cholangiocarcinoma, including the heterogeneous landscape of immune cells within the tumour microenvironment, the immunomodulatory effect of the microbiota and IDH1 mutations, and the association of immune-related signatures and patient outcomes. We introduce findings from preclinical immunotherapy studies, discuss future immune-mediated treatment options, and provide a summary of results from clinical trials testing immune-based approaches in patients with cholangiocarcinoma. This Review provides a thorough survey of our knowledge on immune signatures and immunotherapy in cholangiocarcinoma.
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Affiliation(s)
- Tim F Greten
- Gastrointestinal Malignancies Section, Thoracic and Gastrointestinal Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
- Liver Cancer Program, Bethesda, MD, USA.
| | - Robert Schwabe
- Institute of Human Nutrition, Columbia University, New York, NY, USA
- Department of Medicine, Columbia University, New York, NY, USA
| | - Nabeel Bardeesy
- Department of Medicine, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA
- Cancer Program, Broad Institute of Harvard and MIT, Cambridge, MA, USA
| | - Lichun Ma
- Cancer Data Science Laboratory, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - Lipika Goyal
- Division of Oncology, Stanford School of Medicine, Palo Alto, CA, USA
| | - Robin K Kelley
- Department of Medicine, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA
| | - Xin W Wang
- Liver Cancer Program, Bethesda, MD, USA
- Liver Carcinogenesis Section, Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
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Devan AR, Nair B, Aryan MK, Liju VB, Koshy JJ, Mathew B, Valsan A, Kim H, Nath LR. Decoding Immune Signature to Detect the Risk for Early-Stage HCC Recurrence. Cancers (Basel) 2023; 15:2729. [PMID: 37345066 DOI: 10.3390/cancers15102729] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2023] [Revised: 05/02/2023] [Accepted: 05/09/2023] [Indexed: 06/23/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is often recognized as an inflammation-linked cancer, which possesses an immunosuppressive tumor microenvironment. Curative treatments such as surgical resection, liver transplantation, and percutaneous ablation are mainly applicable in the early stage and demonstrate significant improvement of survival rate in most patients. However, 70-80% of patients report HCC recurrence within 5 years of curative treatment, representing an important clinical issue. However, there is no effective recurrence marker after surgical and locoregional therapies, thus, tumor size, number, and histological features such as cancer cell differentiation are often considered as risk factors for HCC recurrence. Host immunity plays a critical role in regulating carcinogenesis, and the immune microenvironment characterized by its composition, functional status, and density undergoes significant alterations in each stage of cancer progression. Recent studies reported that analysis of immune contexture could yield valuable information regarding the treatment response, prognosis and recurrence. This review emphasizes the prognostic value of tumors associated with immune factors in HCC recurrence after curative treatment. In particular, we review the immune landscape and immunological factors contributing to early-stage HCC recurrence, and discuss the immunotherapeutic interventions to prevent tumor recurrence following curative treatments.
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Affiliation(s)
- Aswathy R Devan
- Department of Pharmacognosy, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Kochi 682041, Kerala, India
| | - Bhagyalakshmi Nair
- Department of Pharmacognosy, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Kochi 682041, Kerala, India
| | | | - Vijayastelar B Liju
- The Shraga Segal Department of Microbiology-Immunology and Genetics, Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva 84105, Israel
| | - Joel Joy Koshy
- Department of Pharmacognosy, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Kochi 682041, Kerala, India
| | - Bijo Mathew
- Department of Pharmaceutical Chemistry, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Kochi 682041, Kerala, India
| | - Arun Valsan
- Department of Gastroenterology and Epatology, Amrita Institute of Medical Science, Kochi 682041, Kerala, India
| | - Hoon Kim
- Department of Pharmacy, and Research Institute of Life Pharmaceutical Sciences, Sunchon National University, Suncheon 57922, Republic of Korea
| | - Lekshmi R Nath
- Department of Pharmacognosy, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Kochi 682041, Kerala, India
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20
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Robin A, Mackowiak C, Bost R, Dujardin F, Barbarin A, Thierry A, Hauet T, Pellerin L, Gombert JM, Salamé E, Herbelin A, Barbier L. Early activation and recruitment of invariant natural killer T cells during liver ischemia-reperfusion: the major role of the alarmin interleukin-33. Front Immunol 2023; 14:1099529. [PMID: 37228593 PMCID: PMC10203422 DOI: 10.3389/fimmu.2023.1099529] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Accepted: 04/12/2023] [Indexed: 05/27/2023] Open
Abstract
Over the past thirty years, the complexity of the αβ-T cell compartment has been enriched by the identification of innate-like T cells (ITCs), which are composed mainly of invariant natural killer T (iNKT) cells and mucosal-associated invariant T (MAIT) cells. Based on animal studies using ischemia-reperfusion (IR) models, a key role has been attributed to iNKT cells in close connection with the alarmin/cytokine interleukin (IL)-33, as early sensors of cell-stress in the initiation of acute sterile inflammation. Here we have investigated whether the new concept of a biological axis of circulating iNKT cells and IL-33 applies to humans, and may be extended to other ITC subsets, namely MAIT and γδ-T cells, in the acute sterile inflammation sequence occurring during liver transplant (LT). From a prospective biological collection of recipients, we reported that LT was accompanied by an early and preferential activation of iNKT cells, as attested by almost 40% of cells having acquired the expression of CD69 at the end of LT (i.e. 1-3 hours after portal reperfusion), as opposed to only 3-4% of conventional T cells. Early activation of iNKT cells was positively correlated with the systemic release of the alarmin IL-33 at graft reperfusion. Moreover, in a mouse model of hepatic IR, iNKT cells were activated in the periphery (spleen), and recruited in the liver in WT mice, as early as the first hour after reperfusion, whereas this phenomenon was virtually missing in IL-33-deficient mice. Although to a lesser degree than iNKT cells, MAIT and γδ-T cells also seemed targeted during LT, as attested by 30% and 10% of them acquiring CD69 expression, respectively. Like iNKT cells, and in clear contrast to γδ-T cells, activation of MAIT cells during LT was closely associated with both release of IL-33 immediately after graft reperfusion and severity of liver dysfunction occurring during the first three post-operative days. All in all, this study identifies iNKT and MAIT cells in connection with IL-33 as new key cellular factors and mechanisms of acute sterile inflammation in humans. Further investigations are required to confirm the implication of MAIT and iNKT cell subsets, and to precisely assess their functions, in the clinical course of sterile inflammation accompanying LT.
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Affiliation(s)
- Aurélie Robin
- Centre Hospitalier Universitaire de Poitiers, Institut National de la Santé Et de la Recherche Médicale, Ischemie Reperfusion Métabolisme et Inflammation Stérile en Transplantation, Université de Poitiers, Poitiers, France
| | - Claire Mackowiak
- Institut National de la Santé Et de la Recherche Médicale (INSERM), Ischemie Reperfusion Métabolisme et Inflammation Stérile en Transplantation (IRMETIST), Université de Poitiers, Poitiers, France
| | - Romain Bost
- Institut National de la Santé Et de la Recherche Médicale (INSERM), Ischemie Reperfusion Métabolisme et Inflammation Stérile en Transplantation (IRMETIST), Université de Poitiers, Poitiers, France
| | - Fanny Dujardin
- Centre Hospitalier Universitaire (CHU) Trousseau, Pathology, Tours, France
| | - Alice Barbarin
- Centre Hospitalier Universitaire de Poitiers, Institut National de la Santé Et de la Recherche Médicale, Ischemie Reperfusion Métabolisme et Inflammation Stérile en Transplantation, Université de Poitiers, Poitiers, France
| | - Antoine Thierry
- Université de Poitiers, Institut National de la Santé Et de la Recherche Médicale (INSERM), Ischemie Reperfusion Métabolisme et Inflammation Stérile en Transplantation (IRMETIST), Centre Hospitalier Universitaire (CHU) de Poitiers, Nephrology, Poitiers, France
| | - Thierry Hauet
- Université de Poitiers, Institut National de la Santé Et de la Recherche Médicale (INSERM), Ischemie Reperfusion Métabolisme et Inflammation Stérile en Transplantation (IRMETIST), Centre Hospitalier Universitaire (CHU) de Poitiers, Biochemistry, Poitiers, France
| | - Luc Pellerin
- Université de Poitiers, Institut National de la Santé Et de la Recherche Médicale (INSERM), Ischemie Reperfusion Métabolisme et Inflammation Stérile en Transplantation (IRMETIST), Centre Hospitalier Universitaire (CHU) de Poitiers, Biochemistry, Poitiers, France
| | - Jean-Marc Gombert
- Université de Poitiers, Institut National de la Santé Et de la Recherche Médicale (INSERM), Ischemie Reperfusion Métabolisme et Inflammation Stérile en Transplantation (IRMETIST), Centre Hospitalier Universitaire (CHU) de Poitiers, Immunology, Poitiers, France
| | - Ephrem Salamé
- Université de Tours, Centre Hospitalier Universitaire (CHU) Trousseau, Digestive Surgery and Liver Transplantation, Institut National de la Santé Et de la Recherche Médicale (INSERM), Ischemie Reperfusion Métabolisme et Inflammation Stérile en Transplantation (IRMETIST), Tours, France
| | - André Herbelin
- Institut National de la Santé Et de la Recherche Médicale (INSERM), Ischemie Reperfusion Métabolisme et Inflammation Stérile en Transplantation (IRMETIST), Université de Poitiers, Poitiers, France
| | - Louise Barbier
- Université de Tours, Centre Hospitalier Universitaire (CHU) Trousseau, Digestive Surgery and Liver Transplantation, Institut National de la Santé Et de la Recherche Médicale (INSERM), Ischemie Reperfusion Métabolisme et Inflammation Stérile en Transplantation (IRMETIST), Tours, France
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21
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Heymann F, Mossanen JC, Peiseler M, Niemietz PM, Araujo David B, Krenkel O, Liepelt A, Batista Carneiro M, Kohlhepp MS, Kubes P, Tacke F. Hepatic C-X-C chemokine receptor type 6-expressing innate lymphocytes limit detrimental myeloid hyperactivation in acute liver injury. Hepatol Commun 2023; 7:e0102. [PMID: 36972392 PMCID: PMC10503691 DOI: 10.1097/hc9.0000000000000102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Accepted: 01/28/2023] [Indexed: 03/29/2023] Open
Abstract
BACKGROUND Acute liver failure (ALF) is characterized by rapid clinical deterioration and high mortality. Acetaminophen (APAP or paracetamol) overdose is a leading cause of ALF, resulting in hepatocellular necrosis with subsequent inflammation, inflicting further liver damage. Infiltrating myeloid cells are early drivers of liver inflammation. However, the role of the abundant population of liver-resident innate lymphocytes, which commonly express the chemokine receptor CXCR6, is incompletely understood in ALF. METHODS We investigated the role of CXCR6-expressing innate lymphocytes using the model of acute APAP toxicity in mice deficient in CXCR6 (Cxcr6gfp/gfp). RESULTS APAP-induced liver injury was strongly aggravated in Cxcr6gfp/gfp mice compared with wild-type counterparts. Immunophenotyping using flow cytometry revealed a reduction in liver CD4+T cells, natural killer (NK) cells, and most prominently, NKT cells, whereas CXCR6 was dispensable for CD8+ T-cell accumulation. CXCR6-deficient mice exhibited excessive neutrophil and inflammatory macrophage infiltration. Intravital microscopy revealed dense cellular clusters of neutrophils in necrotic liver tissue, with higher numbers of clustering neutrophils in Cxcr6gfp/gfp mice. Gene expression analysis linked hyperinflammation in CXCR6 deficiency to increased IL-17 signaling. Although reduced in overall numbers, CXCR6-deficient mice had a shift in NKT cell subsets with increased RORγt-expressing NKT17 cells as a likely source of IL-17. In patients with ALF, we found a prominent accumulation of IL-17-expressing cells. Accordingly, CXCR6-deficient mice lacking IL-17 (Cxcr6gfp/gfpx Il17-/-) had ameliorated liver damage and reduced inflammatory myeloid infiltrates. CONCLUSIONS Our study identifies a crucial role of CXCR6-expressing liver innate lymphocytes as orchestrators in acute liver injury containing IL-17-mediated myeloid cell infiltration. Hence, strengthening the CXCR6-axis or downstream inhibition of IL-17 could yield novel therapeutics in ALF.
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Affiliation(s)
- Felix Heymann
- Department of Hepatology & Gastroenterology, Charité Universitätsmedizin Berlin, Campus Virchow Klinikum and Campus Charité Mitte, Berlin, Germany
| | - Jana C. Mossanen
- Department of Intensive and Intermediate Care, University Hospital Aachen, Aachen, Germany
| | - Moritz Peiseler
- Department of Hepatology & Gastroenterology, Charité Universitätsmedizin Berlin, Campus Virchow Klinikum and Campus Charité Mitte, Berlin, Germany
- Berlin Institute of Health (BIH), Berlin, Germany
| | | | - Bruna Araujo David
- Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Oliver Krenkel
- Department of Medicine III, University Hospital Aachen, Aachen, Germany
| | - Anke Liepelt
- Department of Medicine III, University Hospital Aachen, Aachen, Germany
| | - Matheus Batista Carneiro
- Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Marlene S. Kohlhepp
- Department of Hepatology & Gastroenterology, Charité Universitätsmedizin Berlin, Campus Virchow Klinikum and Campus Charité Mitte, Berlin, Germany
| | - Paul Kubes
- Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Frank Tacke
- Department of Hepatology & Gastroenterology, Charité Universitätsmedizin Berlin, Campus Virchow Klinikum and Campus Charité Mitte, Berlin, Germany
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22
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Tian P, Yang W, Guo X, Wang T, Tan S, Sun R, Xiao R, Wang Y, Jiao D, Xu Y, Wei Y, Wu Z, Li C, Gao L, Ma C, Liang X. Early life gut microbiota sustains liver-resident natural killer cells maturation via the butyrate-IL-18 axis. Nat Commun 2023; 14:1710. [PMID: 36973277 PMCID: PMC10043027 DOI: 10.1038/s41467-023-37419-7] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Accepted: 03/16/2023] [Indexed: 03/29/2023] Open
Abstract
Liver-resident natural killer cells, a unique lymphocyte subset in liver, develop locally and play multifaceted immunological roles. However, the mechanisms for the maintenance of liver-resident natural killer cell homeostasis remain unclear. Here we show that early-life antibiotic treatment blunt functional maturation of liver-resident natural killer cells even at adulthood, which is dependent on the durative microbiota dysbiosis. Mechanistically, early-life antibiotic treatment significantly decreases butyrate level in liver, and subsequently led to defective liver-resident natural killer cell maturation in a cell-extrinsic manner. Specifically, loss of butyrate impairs IL-18 production in Kupffer cells and hepatocytes through acting on the receptor GPR109A. Disrupted IL-18/IL-18R signaling in turn suppresses the mitochondrial activity and the functional maturation of liver-resident natural killer cells. Strikingly, dietary supplementation of experimentally or clinically used Clostridium butyricum restores the impaired liver-resident natural killer cell maturation and function induced by early-life antibiotic treatment. Our findings collectively unmask a regulatory network of gut-liver axis, highlighting the importance of the early-life microbiota in the development of tissue-resident immune cells.
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Affiliation(s)
- Panpan Tian
- Key Laboratory for Experimental Teratology of Ministry of Education, Key Laboratory of Infection and Immunity of Shandong Province and Department of Immunology, School of Basic Medical Sciences, Cheeloo Medical College of Shandong University, Jinan, 250012, Shandong, China
| | - Wenwen Yang
- Key Laboratory for Experimental Teratology of Ministry of Education, Key Laboratory of Infection and Immunity of Shandong Province and Department of Immunology, School of Basic Medical Sciences, Cheeloo Medical College of Shandong University, Jinan, 250012, Shandong, China
| | - Xiaowei Guo
- Key Laboratory for Experimental Teratology of Ministry of Education, Key Laboratory of Infection and Immunity of Shandong Province and Department of Immunology, School of Basic Medical Sciences, Cheeloo Medical College of Shandong University, Jinan, 250012, Shandong, China
| | - Tixiao Wang
- Key Laboratory for Experimental Teratology of Ministry of Education, Key Laboratory of Infection and Immunity of Shandong Province and Department of Immunology, School of Basic Medical Sciences, Cheeloo Medical College of Shandong University, Jinan, 250012, Shandong, China
| | - Siyu Tan
- Key Laboratory for Experimental Teratology of Ministry of Education, Key Laboratory of Infection and Immunity of Shandong Province and Department of Immunology, School of Basic Medical Sciences, Cheeloo Medical College of Shandong University, Jinan, 250012, Shandong, China
| | - Renhui Sun
- Key Laboratory for Experimental Teratology of Ministry of Education, Key Laboratory of Infection and Immunity of Shandong Province and Department of Immunology, School of Basic Medical Sciences, Cheeloo Medical College of Shandong University, Jinan, 250012, Shandong, China
| | - Rong Xiao
- Key Laboratory for Experimental Teratology of Ministry of Education, Key Laboratory of Infection and Immunity of Shandong Province and Department of Immunology, School of Basic Medical Sciences, Cheeloo Medical College of Shandong University, Jinan, 250012, Shandong, China
| | - Yuzhen Wang
- Key Laboratory for Experimental Teratology of Ministry of Education, Key Laboratory of Infection and Immunity of Shandong Province and Department of Immunology, School of Basic Medical Sciences, Cheeloo Medical College of Shandong University, Jinan, 250012, Shandong, China
| | - Deyan Jiao
- Key Laboratory for Experimental Teratology of Ministry of Education, Key Laboratory of Infection and Immunity of Shandong Province and Department of Immunology, School of Basic Medical Sciences, Cheeloo Medical College of Shandong University, Jinan, 250012, Shandong, China
| | - Yachen Xu
- Key Laboratory for Experimental Teratology of Ministry of Education, Key Laboratory of Infection and Immunity of Shandong Province and Department of Immunology, School of Basic Medical Sciences, Cheeloo Medical College of Shandong University, Jinan, 250012, Shandong, China
| | - Yanfei Wei
- Key Laboratory for Experimental Teratology of Ministry of Education, Key Laboratory of Infection and Immunity of Shandong Province and Department of Immunology, School of Basic Medical Sciences, Cheeloo Medical College of Shandong University, Jinan, 250012, Shandong, China
| | - Zhuanchang Wu
- Key Laboratory for Experimental Teratology of Ministry of Education, Key Laboratory of Infection and Immunity of Shandong Province and Department of Immunology, School of Basic Medical Sciences, Cheeloo Medical College of Shandong University, Jinan, 250012, Shandong, China
- Collaborative Innovation Center of Technology and Equipment for Biological Diagnosis and Therapy in Universities of Shandong, Jinan, 250012, Shandong, China
| | - Chunyang Li
- Key Laboratory for Experimental Teratology of Ministry of Education, Department of Histology and Embryology, School of Basic Medical Science, Shandong University, Jinan, China
| | - Lifen Gao
- Key Laboratory for Experimental Teratology of Ministry of Education, Key Laboratory of Infection and Immunity of Shandong Province and Department of Immunology, School of Basic Medical Sciences, Cheeloo Medical College of Shandong University, Jinan, 250012, Shandong, China
- Collaborative Innovation Center of Technology and Equipment for Biological Diagnosis and Therapy in Universities of Shandong, Jinan, 250012, Shandong, China
| | - Chunhong Ma
- Key Laboratory for Experimental Teratology of Ministry of Education, Key Laboratory of Infection and Immunity of Shandong Province and Department of Immunology, School of Basic Medical Sciences, Cheeloo Medical College of Shandong University, Jinan, 250012, Shandong, China.
- Collaborative Innovation Center of Technology and Equipment for Biological Diagnosis and Therapy in Universities of Shandong, Jinan, 250012, Shandong, China.
| | - Xiaohong Liang
- Key Laboratory for Experimental Teratology of Ministry of Education, Key Laboratory of Infection and Immunity of Shandong Province and Department of Immunology, School of Basic Medical Sciences, Cheeloo Medical College of Shandong University, Jinan, 250012, Shandong, China.
- Collaborative Innovation Center of Technology and Equipment for Biological Diagnosis and Therapy in Universities of Shandong, Jinan, 250012, Shandong, China.
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23
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Yang L, Hao Y, Boeckmans J, Rodrigues RM, He Y. Immune cells and their derived microRNA-enriched extracellular vesicles in nonalcoholic fatty liver diseases: Novel therapeutic targets. Pharmacol Ther 2023; 243:108353. [PMID: 36738973 DOI: 10.1016/j.pharmthera.2023.108353] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Revised: 01/09/2023] [Accepted: 01/30/2023] [Indexed: 02/05/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease worldwide. Despite extensive research and multiple clinical trials, there are still no FDA-approved therapies to treat the most severe forms of NAFLD. This is largely due to its complicated etiology and pathogenesis, which involves visceral obesity, insulin resistance, gut dysbiosis, etc. Although inflammation is generally believed to be one of the critical factors that drive the progression of simple steatosis to nonalcoholic steatohepatitis (NASH), the exact type of inflammation and how it contributes to NASH pathogenesis remain largely unknown. Liver inflammation is accompanied by the elevation of inflammatory mediators, including cytokines and chemokines and consequently intrahepatic infiltration of multiple types of immune cells. Recent studies revealed that extracellular vesicles (EVs) derived from inflammatory cells and hepatocytes play an important role in controlling liver inflammation during NASH. In this review, we highlight the roles of innate and adaptive immune cells and their microRNA-enriched EVs during NAFLD development and discuss potential drugs that target inflammatory pathways for the treatment of NAFLD.
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Affiliation(s)
- Liu Yang
- Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai, China; University of Chinese Academy of Sciences, Beijing, China
| | - Yawen Hao
- Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai, China; University of Chinese Academy of Sciences, Beijing, China
| | - Joost Boeckmans
- Department of In Vitro Toxicology and Dermato-Cosmetology, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Brussels, Belgium
| | - Robim M Rodrigues
- Department of In Vitro Toxicology and Dermato-Cosmetology, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Brussels, Belgium.
| | - Yong He
- Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai, China; University of Chinese Academy of Sciences, Beijing, China.
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24
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Hov JR, Karlsen TH. The microbiota and the gut-liver axis in primary sclerosing cholangitis. Nat Rev Gastroenterol Hepatol 2023; 20:135-154. [PMID: 36352157 DOI: 10.1038/s41575-022-00690-y] [Citation(s) in RCA: 30] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/13/2022] [Indexed: 11/11/2022]
Abstract
Primary sclerosing cholangitis (PSC) offers unique opportunities to explore the gut-liver axis owing to the close association between liver disease and colonic inflammation. It is well established that the gut microbiota in people with PSC differs from that of healthy individuals, but details of the microbial factors that demarcate PSC from inflammatory bowel disease (IBD) without PSC are poorly understood. In this Review, we aim to provide an overview of the latest literature on the gut microbiome in PSC and PSC with IBD, critically examining hypotheses on how microorganisms could contribute to the pathogenesis of PSC. A particular emphasis will be put on pathogenic features of the gut microbiota that might explain the occurrence of bile duct inflammation and liver disease in the context of IBD, and we postulate the potential existence of a specific yet unknown factor related to the gut-liver axis as causative in PSC. Available data are scrutinized in the perspective of therapeutic approaches related to the gut-liver axis.
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Affiliation(s)
- Johannes R Hov
- Norwegian PSC Research Center and Section of gastroenterology and Research Institute of Internal Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Oslo, Norway.,Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Tom H Karlsen
- Norwegian PSC Research Center and Section of gastroenterology and Research Institute of Internal Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Oslo, Norway. .,Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
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25
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Kharbanda KK, Chokshi S, Tikhanovich I, Weinman SA, New-Aaron M, Ganesan M, Osna NA. A Pathogenic Role of Non-Parenchymal Liver Cells in Alcohol-Associated Liver Disease of Infectious and Non-Infectious Origin. BIOLOGY 2023; 12:255. [PMID: 36829532 PMCID: PMC9953685 DOI: 10.3390/biology12020255] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Revised: 01/30/2023] [Accepted: 02/02/2023] [Indexed: 02/08/2023]
Abstract
Now, much is known regarding the impact of chronic and heavy alcohol consumption on the disruption of physiological liver functions and the induction of structural distortions in the hepatic tissues in alcohol-associated liver disease (ALD). This review deliberates the effects of alcohol on the activity and properties of liver non-parenchymal cells (NPCs), which are either residential or infiltrated into the liver from the general circulation. NPCs play a pivotal role in the regulation of organ inflammation and fibrosis, both in the context of hepatotropic infections and in non-infectious settings. Here, we overview how NPC functions in ALD are regulated by second hits, such as gender and the exposure to bacterial or viral infections. As an example of the virus-mediated trigger of liver injury, we focused on HIV infections potentiated by alcohol exposure, since this combination was only limitedly studied in relation to the role of hepatic stellate cells (HSCs) in the development of liver fibrosis. The review specifically focusses on liver macrophages, HSC, and T-lymphocytes and their regulation of ALD pathogenesis and outcomes. It also illustrates the activation of NPCs by the engulfment of apoptotic bodies, a frequent event observed when hepatocytes are exposed to ethanol metabolites and infections. As an example of such a double-hit-induced apoptotic hepatocyte death, we deliberate on the hepatotoxic accumulation of HIV proteins, which in combination with ethanol metabolites, causes intensive hepatic cell death and pro-fibrotic activation of HSCs engulfing these HIV- and malondialdehyde-expressing apoptotic hepatocytes.
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Affiliation(s)
- Kusum K. Kharbanda
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
- Department of Biochemistry & Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Shilpa Chokshi
- Institute of Hepatology, Foundation for Liver Research, London SE5 9NT, UK
- Faculty of Life Sciences and Medicine, King’s College London, London SE5 8AF, UK
| | - Irina Tikhanovich
- Department of Internal Medicine, University of Kansas Medical Center, Kansas City, MO 66160, USA
| | - Steven A. Weinman
- Department of Internal Medicine, University of Kansas Medical Center, Kansas City, MO 66160, USA
- Research Service, Kansas City Veterans Administration Medical Center, Kansas City, MO 64128, USA
| | - Moses New-Aaron
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Murali Ganesan
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Natalia A. Osna
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
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26
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Liang J, Bai Y, Ha FS, Luo Y, Deng HT, Gao YT. Combining local regional therapy and systemic therapy: Expected changes in the treatment landscape of recurrent hepatocellular carcinoma. World J Gastrointest Oncol 2023; 15:1-18. [PMID: 36684055 PMCID: PMC9850755 DOI: 10.4251/wjgo.v15.i1.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2022] [Revised: 12/06/2022] [Accepted: 12/28/2022] [Indexed: 01/10/2023] Open
Abstract
Improvements in early screening, new diagnostic techniques, and surgical treatment have led to continuous downward trends in hepatocellular carcinoma (HCC) morbidity and mortality rates. However, high recurrence and refractory cancer after hepatectomy remain important factors affecting the long-term prognosis of HCC. The clinical characteristics and prognosis of recurrent HCC are heterogeneous, and guidelines on treatment strategies for recurrent HCC are lacking. Therapies such as surgical resection, radiofrequency ablation, and transhepatic arterial chemoembolization are effective for tumors confined to the liver, and targeted therapy is a very important treatment for unresectable recurrent HCC with systemic metastasis. With the deepening of the understanding of the immune microenvironment of HCC, blocking immune checkpoints to enhance the antitumor immune response has become a new direction for the treatment of HCC. In addition, improvements in the tumor immune microenvironment caused by local treatment may provide an opportunity to improve the therapeutic effect of HCC treatment. Ongoing and future clinical trial data of combined therapy may develop the new treatment scheme for recurrent HCC. This paper reviews the pattern of recurrent HCC and the characteristics of the immune microenvironment, demonstrates the basis for combining local treatment and systemic treatment, and reports current evidence to better understand current progress and future approaches in the treatment of recurrent HCC.
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Affiliation(s)
- Jing Liang
- Department of Hepatology, Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Nankai University Affiliated Third Center Hospital, Tianjin 300170, China
| | - Yi Bai
- Department of Hepatobiliary Surgery, Tianjin First Central Hospital, Tianjin 300192, China
| | - Fu-Shuang Ha
- Department of Hepatology, Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Nankai University Affiliated Third Center Hospital, Tianjin 300170, China
| | - Ying Luo
- Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Nankai University Affiliated Third Center Hospital, Tianjin 300170, China
| | - Hui-Ting Deng
- Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Nankai University Affiliated Third Center Hospital, Tianjin 300170, China
| | - Ying-Tang Gao
- Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Nankai University Affiliated Third Center Hospital, Tianjin 300170, China
- Tianjin Institute of Hepatobiliary Disease, The Third Central Clinical College of Tianjin Medical University, Tianjin 300170, China
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27
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Chen L, Yuan L, Yang J, Pan Y, Wang H. Identification of key immune-related genes associated with LPS/D-GalN-induced acute liver failure in mice based on transcriptome sequencing. PeerJ 2023; 11:e15241. [PMID: 37168540 PMCID: PMC10166078 DOI: 10.7717/peerj.15241] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Accepted: 03/28/2023] [Indexed: 05/13/2023] Open
Abstract
Background The aim of this study was to identify key immune-related genes in acute liver failure (ALF) by constructing an ALF mouse model for transcriptome sequencing. Methods The C57BL/6 mouse with ALF model was induced by lipopolysaccharide (LPS)/ D-galactosamine (D-GalN). After successful modelling, the liver tissues of all mice were obtained for transcriptome sequencing. The key immune-related genes in mice with ALF were identified by differential expression analysis, immune infiltration analysis, weighted gene co-expression network analysis (WGCNA), enrichment analysis, and protein-protein interaction (PPI) analysis. Results An LPS/D-GalN-induced ALF mouse model was successfully constructed, and transcriptome sequencing was performed. Significant differences in the proportions of monocytes, macrophages M0, macrophages M1 and neutrophils were shown by immune infiltration analysis, and 5255 genes highly associated with these four immune cells were identified by WGCNA. These immune genes were found to be significantly enriched in the TNF signalling pathway by enrichment analysis. Finally, PPI analysis was performed on genes enriched in this pathway and three key genes (CXCL1, CXCL10 and IL1B) were screened out and revealed to be significantly upregulated in ALF. Conclusions Key immune-related genes in ALF were identified in this study, which may provide not only potential therapeutic targets for treating ALF and improving its prognosis, but also a reliable scientific basis for the immunotherapy of the disease.
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Affiliation(s)
- Ling Chen
- Department of Infectious Disease, Zhejiang Hospital, Hangzhou, China
| | - Li Yuan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Jingle Yang
- Department of Infectious Disease, Zhejiang Hospital, Hangzhou, China
| | - Yizhi Pan
- Department of Infectious Disease, Zhejiang Hospital, Hangzhou, China
| | - Hong Wang
- Department of Infectious Disease, Zhejiang Hospital, Hangzhou, China
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28
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Jin X, Bi J. Prospects for NK-based immunotherapy of chronic HBV infection. Front Immunol 2022; 13:1084109. [PMID: 36591230 PMCID: PMC9797727 DOI: 10.3389/fimmu.2022.1084109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2022] [Accepted: 12/01/2022] [Indexed: 12/16/2022] Open
Abstract
Effective and long-term treatment is required for controlling chronic Hepatitis B Virus (HBV) infection. Natural killer (NK) cells are antiviral innate lymphocytes and represent an essential arm of current immunotherapy. In chronic HBV (CHB), NK cells display altered changes in phenotypes and functions, but preserve antiviral activity, especially for cytolytic activity. On the other hand, NK cells might also cause liver injury in the disease. NK -based immunotherapy, including adoptive NK cell therapy and NK -based checkpoint inhibition, could potentially exploit the antiviral aspect of NK cells for controlling CHB infection while preventing liver tissue damage. Here, we review recent progress in NK cell biology under the context of CHB infection, and discuss potential NK -based immunotherapy strategies for the disease.
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29
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Han HT, Jin WL, Li X. Mesenchymal stem cells-based therapy in liver diseases. MOLECULAR BIOMEDICINE 2022; 3:23. [PMID: 35895169 PMCID: PMC9326420 DOI: 10.1186/s43556-022-00088-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Accepted: 06/20/2022] [Indexed: 12/24/2022] Open
Abstract
Multiple immune cells and their products in the liver together form a complex and unique immune microenvironment, and preclinical models have demonstrated the importance of imbalances in the hepatic immune microenvironment in liver inflammatory diseases and immunocompromised liver diseases. Various immunotherapies have been attempted to modulate the hepatic immune microenvironment for the purpose of treating liver diseases. Mesenchymal stem cells (MSCs) have a comprehensive and plastic immunomodulatory capacity. On the one hand, they have been tried for the treatment of inflammatory liver diseases because of their excellent immunosuppressive capacity; On the other hand, MSCs have immune-enhancing properties in immunocompromised settings and can be modified into cellular carriers for targeted transport of immune enhancers by genetic modification, physical and chemical loading, and thus they are also used in the treatment of immunocompromised liver diseases such as chronic viral infections and hepatocellular carcinoma. In this review, we discuss the immunological basis and recent strategies of MSCs for the treatment of the aforementioned liver diseases. Specifically, we update the immune microenvironment of the liver and summarize the distinct mechanisms of immune microenvironment imbalance in inflammatory diseases and immunocompromised liver diseases, and how MSCs can fully exploit their immunotherapeutic role in liver diseases with both immune imbalance patterns.
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30
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Li Q, Chen F, Wang F. The immunological mechanisms and therapeutic potential in drug-induced liver injury: lessons learned from acetaminophen hepatotoxicity. Cell Biosci 2022; 12:187. [PMID: 36414987 PMCID: PMC9682794 DOI: 10.1186/s13578-022-00921-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Accepted: 11/01/2022] [Indexed: 11/24/2022] Open
Abstract
Acute liver failure caused by drug overdose is a significant clinical problem in developed countries. Acetaminophen (APAP), a widely used analgesic and antipyretic drug, but its overdose can cause acute liver failure. In addition to APAP-induced direct hepatotoxicity, the intracellular signaling mechanisms of APAP-induced liver injury (AILI) including metabolic activation, mitochondrial oxidant stress and proinflammatory response further affect progression and severity of AILI. Liver inflammation is a result of multiple interactions of cell death molecules, immune cell-derived cytokines and chemokines, as well as damaged cell-released signals which orchestrate hepatic immune cell infiltration. The immunoregulatory interplay of these inflammatory mediators and switching of immune responses during AILI lead to different fate of liver pathology. Thus, better understanding the complex interplay of immune cell subsets in experimental models and defining their functional involvement in disease progression are essential to identify novel therapeutic targets for the treatment of AILI. Here, this present review aims to systematically elaborate on the underlying immunological mechanisms of AILI, its relevance to immune cells and their effector molecules, and briefly discuss great therapeutic potential based on inflammatory mediators.
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Affiliation(s)
- Qianhui Li
- grid.511083.e0000 0004 7671 2506Division of Gastroenterology, Seventh Affiliated Hospital of Sun Yat-sen University, No.628, Zhenyuan Road, Shenzhen, 518107 China
| | - Feng Chen
- grid.511083.e0000 0004 7671 2506Division of Gastroenterology, Seventh Affiliated Hospital of Sun Yat-sen University, No.628, Zhenyuan Road, Shenzhen, 518107 China
| | - Fei Wang
- grid.511083.e0000 0004 7671 2506Division of Gastroenterology, Seventh Affiliated Hospital of Sun Yat-sen University, No.628, Zhenyuan Road, Shenzhen, 518107 China
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31
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Savchenko AA, Borisov AG, Kudryavtsev IV, Belenjuk VD. DISSEMINATED PURULENT PERITONITIS OUTCOME AFFECTS NKT CELL PHENOTYPE. RUSSIAN JOURNAL OF INFECTION AND IMMUNITY 2022. [DOI: 10.15789/2220-7619-dpp-2004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
The aim of our study was to investigate the main characteristics of peripheral blood NKT cell phenotype in patients with disseminated purulent peritonitis (DPP) in dynamics of postoperative period, depending on the disease outcome. Fifty-two patients with acute surgical diseases and injuries of the abdominal organs complicated by DPP, and 68 healthy individuals in control group, were examined. Blood sampling was performed before surgery (preoperative period), as well as on the day 7, 14 and 21 of postoperative period. All patients with DPP were divided into two groups depending on disease outcome in postoperative period: patients with favorable disease outcome (n = 34); and patients with unfavorable outcome (n = 18). Study of the phenotype of blood NKT lymphocytes was performed by flow cytometry using direct immunofluorescence of whole peripheral blood samples with monoclonal antibodies. The low relative and absolute level of NKT cells was observed in DPP patients regardless of outcome disease in preoperative period. At the same time, the absolute level of NKT cells returned to normal only in patients with favorable DPP outcome and only by day 21 after surgery. Patients with favorable DPP outcome by the end of examination period had normalized quantity of mature NKT-lymphocytes and significantly decreased level of cytotoxic cells which was apparently associated with migration of such cell subsets to site of inflammation. A reduced level of non-classical (expressing CD8 marker) mature and cytokine-producing NKT cells was detected only in patients with favorable DPP outcome in preoperative period which returned to normal by the end of postoperative period. At the same time, patients with unfavorable disease outcome had reduced quantity of NKT cells of these subsets by day 21 of postoperative treatment. Patients with favorable outcome had high level of mature and cytotoxic CD11b+ NKT cells already in the preoperative period, while patients with unfavorable DPP outcome had increased level of cytotoxic CD11b+ NKT cells only by day 21 after surgery. The proportion of NKT cells expressing activation markers (CD28 and CD57) was reduced in patients in preoperative period that returned to normal immediately after surgery with favorable outcome, while it recovered with unfavorable outcome closer to the end of postoperative examination. The defined features of NKT cell phenotype in patients with unfavorable DPP outcome characterize disturbances in subset ratio and mechanisms of functioning of this cell fraction. This determines a need to develop immunotherapeutic methods aimed at stimulating immunoregulatory activity of NKT cells.
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32
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Jiang T, Sun W, Aji T, Shao Y, Guo C, Zhang C, Ran B, Hou J, Yasen A, Guo Q, Wang H, Qu K, Wen H. Single-Cell Heterogeneity of the Liver-Infiltrating Lymphocytes in Individuals with Chronic Echinococcus multilocularis Infection. Infect Immun 2022; 90:e0017722. [PMID: 36317875 PMCID: PMC9670881 DOI: 10.1128/iai.00177-22] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Accepted: 09/16/2022] [Indexed: 11/05/2022] Open
Abstract
Human alveolar echinococcosis (AE) is a tumor-like disease predominantly located in the liver. The cellular composition and heterogeneity of the lesion-infiltrating lymphocytes which produce an "immunosuppressive" microenvironment are poorly understood. Here, we profiled 83,921 CD45+ lymphocytes isolated from the peripheral blood (PB), perilesion (PL), and adjacent normal (AN) liver tissue of four advanced-stage AE patients using single-cell RNA and T-cell receptor (TCR) sequencing technology. We identified 23 large clusters, and the distributions and transcriptomes of these cell clusters in the liver and periphery were different. The cellular proportions of exhausted CD8+ T cells and group 2 innate lymphoid cells (ILC2s) were notably higher in PL tissue, and the expression features of these cell subsets were related to neoplasm metastasis and immune response suppression. In the 5 CD8+ T-cell populations, only CD8+ mucosa-associated invariant T (MAIT) cells were enriched in PL samples and the TRAV1-2_TRAJ33_TRAC TCR was clonally expanded. In the 11 subsets of CD4+ T cells, Th17 cells and induced regulatory T cells (iTregs) were preferentially enriched in PL samples, and their highly expressed genes were related to cell invasion, tumor metastasis, and inhibition of the inflammatory immune response. Exhaustion-specific genes (TIGIT, PD-1, and CTLA4) were upregulated in Tregs. Interestingly, there was a close contact between CD8+ T cells and iTregs or Th17 cells, especially for genes related to immunosuppression, such as PDCD1-FAM3C, which were highly expressed in PL tissue. This transcriptional data set provides valuable insights and a rich resource for deeply understanding the immune microenvironment in AE, which could provide potential target signatures for AE diagnosis and immunotherapies.
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Affiliation(s)
- Tiemin Jiang
- State Key Laboratory of Pathogenesis, Prevention and Management of High Incidence Diseases in Central Asia, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Wujianan Sun
- Department of Oncology, The First Affiliated Hospital of USTC, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Tuerganaili Aji
- Department of Hepatobiliary and Echinococcosis Surgery, Digestive and Vascular Surgery Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Yingmei Shao
- Department of Hepatobiliary and Echinococcosis Surgery, Digestive and Vascular Surgery Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Chuang Guo
- Department of Oncology, The First Affiliated Hospital of USTC, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Chuanshan Zhang
- State Key Laboratory of Pathogenesis, Prevention and Management of High Incidence Diseases in Central Asia, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Bo Ran
- Department of Hepatobiliary and Echinococcosis Surgery, Digestive and Vascular Surgery Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Jiao Hou
- State Key Laboratory of Pathogenesis, Prevention and Management of High Incidence Diseases in Central Asia, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Aimaiti Yasen
- State Key Laboratory of Pathogenesis, Prevention and Management of High Incidence Diseases in Central Asia, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Qiang Guo
- Department of Hepatobiliary and Echinococcosis Surgery, Digestive and Vascular Surgery Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Hui Wang
- State Key Laboratory of Pathogenesis, Prevention and Management of High Incidence Diseases in Central Asia, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Kun Qu
- Department of Oncology, The First Affiliated Hospital of USTC, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
- School of Data Science, University of Science and Technology of China, Hefei, China
| | - Hao Wen
- State Key Laboratory of Pathogenesis, Prevention and Management of High Incidence Diseases in Central Asia, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
- Department of Hepatobiliary and Echinococcosis Surgery, Digestive and Vascular Surgery Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
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33
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Choi SE, Jeong WI. Innate Lymphoid Cells: New Culprits of Alcohol-Associated Steatohepatitis. Cell Mol Gastroenterol Hepatol 2022; 15:279-280. [PMID: 36334655 PMCID: PMC9793251 DOI: 10.1016/j.jcmgh.2022.10.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2022] [Revised: 10/14/2022] [Accepted: 10/17/2022] [Indexed: 11/22/2022]
Affiliation(s)
| | - Won-Il Jeong
- Laboratory of Liver Research, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea.
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34
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Sun B, Chen L, Tang E, Lin M. The immuno-therapeutic potential of miR-2392 in patients with hepatocellular carcinoma. Liver Int 2022; 42:2585-2586. [PMID: 35962762 DOI: 10.1111/liv.15395] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Accepted: 08/11/2022] [Indexed: 02/13/2023]
Affiliation(s)
- Bin Sun
- Center for Clinical Research and Translational Medicine, Yangpu Hospital, Tongji University School of Medicine, Shanghai, P. R. China.,Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Navy Military Medical University, Shanghai, P. R. China
| | - Lei Chen
- Center for Clinical Research and Translational Medicine, Yangpu Hospital, Tongji University School of Medicine, Shanghai, P. R. China.,Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Navy Military Medical University, Shanghai, P. R. China
| | - Erjiang Tang
- Center for Clinical Research and Translational Medicine, Yangpu Hospital, Tongji University School of Medicine, Shanghai, P. R. China
| | - Moubin Lin
- Center for Clinical Research and Translational Medicine, Yangpu Hospital, Tongji University School of Medicine, Shanghai, P. R. China.,Department of General Surgery, Yangpu Hospital, Tongji University School of Medicine, Shanghai, P. R. China
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35
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Gu X, Chu Q, Ma X, Wang J, Chen C, Guan J, Ren Y, Wu S, Zhu H. New insights into iNKT cells and their roles in liver diseases. Front Immunol 2022; 13:1035950. [PMID: 36389715 PMCID: PMC9643775 DOI: 10.3389/fimmu.2022.1035950] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2022] [Accepted: 10/14/2022] [Indexed: 08/29/2023] Open
Abstract
Natural killer T cells (NKTs) are an important part of the immune system. Since their discovery in the 1990s, researchers have gained deeper insights into the physiology and functions of these cells in many liver diseases. NKT cells are divided into two subsets, type I and type II. Type I NKT cells are also named iNKT cells as they express a semi-invariant T cell-receptor (TCR) α chain. As part of the innate immune system, hepatic iNKT cells interact with hepatocytes, macrophages (Kupffer cells), T cells, and dendritic cells through direct cell-to-cell contact and cytokine secretion, bridging the innate and adaptive immune systems. A better understanding of hepatic iNKT cells is necessary for finding new methods of treating liver disease including autoimmune liver diseases, alcoholic liver diseases (ALDs), non-alcoholic fatty liver diseases (NAFLDs), and liver tumors. Here we summarize how iNKT cells are activated, how they interact with other cells, and how they function in the presence of liver disease.
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Affiliation(s)
- Xinyu Gu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Qingfei Chu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xiao Ma
- Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Jing Wang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Chao Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jun Guan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yanli Ren
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Shanshan Wu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Haihong Zhu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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Legaz I, Bolarín JM, Campillo JA, Moya-Quiles MR, Miras M, Muro M, Minguela A, Álvarez-López MR. Killer Cell Immunoglobulin-like Receptors (KIR) and Human Leucocyte Antigen C (HLA-C) Increase the Risk of Long-Term Chronic Liver Graft Rejection. Int J Mol Sci 2022; 23:ijms232012155. [PMID: 36293011 PMCID: PMC9603177 DOI: 10.3390/ijms232012155] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Revised: 10/06/2022] [Accepted: 10/10/2022] [Indexed: 11/16/2022] Open
Abstract
Chronic liver rejection (CR) represents a complex clinical situation because many patients do not respond to increased immunosuppression. Killer cell immunoglobulin-like receptors/Class I Human Leukocyte Antigens (KIR/HLA-I) interactions allow for predicting Natural Killer (NK) cell alloreactivity and influence the acute rejection of liver allograft. However, its meaning in CR liver graft remains controversial. KIR and HLA genotypes were studied in 513 liver transplants using sequence-specific oligonucleotides (PCR-SSO) methods. KIRs, human leucocyte antigen C (HLA-C) genotypes, KIR gene mismatches, and the KIR/HLA-ligand were analyzed and compared in overall transplants with CR (n = 35) and no-chronic rejection (NCR = 478). Activating KIR (aKIR) genes in recipients (rKIR2DS2+ and rKIR2DS3+) increased CR compared with NCR groups (p = 0.013 and p = 0.038). The inhibitory KIR (iKIR) genes in recipients rKIR2DL2+ significantly increased the CR rate compared with their absence (9.1% vs. 3.7%, p = 0.020). KIR2DL3 significantly increases CR (13.1% vs. 5.2%; p = 0.008). There was no influence on NCR. CR was observed in HLA-I mismatches (MM). The absence of donor (d) HLA-C2 ligand (dC2−) ligand increases CR concerning their presence (13.1% vs. 5.6%; p = 0.018). A significant increase of CR was observed in rKIR2DL3+/dC1− (p = 0.015), rKIR2DS4/dC1− (p = 0.014) and rKIR2DL3+/rKIR2DS4+/dC1− (p = 0.006). Long-term patient survival was significantly lower in rKIR2DS1+rKIR2DS4+/dC1− at 5–10 years post-transplant. This study shows the influence of rKIR/dHLA-C combinations and aKIR gene-gene mismatches in increasing CR and KIR2DS1+/C1-ligands and the influence of KIR2DS4+/C1-ligands in long-term graft survival.
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Affiliation(s)
- Isabel Legaz
- Department of Legal and Forensic Medicine, Biomedical Research Institute (IMIB), Regional Campus of International Excellence “Campus Mare Nostrum”, Faculty of Medicine, University of Murcia, 30120 Murcia, Spain
- Correspondence: ; Tel.: +34-868883957; Fax: +34-868834307
| | - Jose Miguel Bolarín
- Department of Legal and Forensic Medicine, Biomedical Research Institute (IMIB), Regional Campus of International Excellence “Campus Mare Nostrum”, Faculty of Medicine, University of Murcia, 30120 Murcia, Spain
| | - Jose Antonio Campillo
- Immunology Service, Instituto Murciano de Investigación biosanitaria (IMIB), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Hospital Clínico Universitario Virgen de la Arrixaca (HCUVA), 30120 Murcia, Spain
| | - María R. Moya-Quiles
- Immunology Service, Instituto Murciano de Investigación biosanitaria (IMIB), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Hospital Clínico Universitario Virgen de la Arrixaca (HCUVA), 30120 Murcia, Spain
| | - Manuel Miras
- Digestive Medicine Service, Hospital Clínico Universitario Virgen de la Arrixaca (HCUVA), 30120 Murcia, Spain
| | - Manuel Muro
- Immunology Service, Instituto Murciano de Investigación biosanitaria (IMIB), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Hospital Clínico Universitario Virgen de la Arrixaca (HCUVA), 30120 Murcia, Spain
| | - Alfredo Minguela
- Immunology Service, Instituto Murciano de Investigación biosanitaria (IMIB), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Hospital Clínico Universitario Virgen de la Arrixaca (HCUVA), 30120 Murcia, Spain
| | - María R. Álvarez-López
- Immunology Service, Instituto Murciano de Investigación biosanitaria (IMIB), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Hospital Clínico Universitario Virgen de la Arrixaca (HCUVA), 30120 Murcia, Spain
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Hoogerland JA, Staels B, Dombrowicz D. Immune-metabolic interactions in homeostasis and the progression to NASH. Trends Endocrinol Metab 2022; 33:690-709. [PMID: 35961913 DOI: 10.1016/j.tem.2022.07.001] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Revised: 07/09/2022] [Accepted: 07/12/2022] [Indexed: 12/16/2022]
Abstract
The incidence of non-alcoholic fatty liver disease (NAFLD) has increased significantly over the past two decades. NAFLD ranges from simple steatosis (NAFL) to nonalcoholic steatohepatitis (NASH) and predisposes to fibrosis and hepatocellular carcinoma (HCC). The importance of the immune system in hepatic physiology and in the progression of NAFLD is increasingly recognized. At homeostasis, the liver participates in immune defense against pathogens and in tolerance of gut-derived microbial compounds. Hepatic immune cells also respond to metabolic stimuli and have a role in NAFLD progression to NASH. In this review, we discuss how metabolic perturbations affect immune cell phenotype and function in NAFL and NASH, and then focus on the role of immune cells in liver homeostasis and in the development of NASH.
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Affiliation(s)
- Joanne A Hoogerland
- Univeristy of Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, F-59000 Lille, France
| | - Bart Staels
- Univeristy of Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, F-59000 Lille, France
| | - David Dombrowicz
- Univeristy of Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, F-59000 Lille, France.
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Raus S, Lopez-Scarim J, Luthy J, Billerbeck E. Hepatic iNKT cells produce type 2 cytokines and restrain antiviral T cells during acute hepacivirus infection. Front Immunol 2022; 13:953151. [PMID: 36159876 PMCID: PMC9501689 DOI: 10.3389/fimmu.2022.953151] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Accepted: 08/22/2022] [Indexed: 12/03/2022] Open
Abstract
Chronic hepatitis C virus (HCV) infection is a curable disease, but the absence of a vaccine remains a major problem in infection prevention. The lack of small animal models and limited access to human liver tissue impede the study of hepatic antiviral immunity and the development of new vaccine strategies. We recently developed an immune-competent mouse model using an HCV-related rodent hepacivirus which shares immunological features with human viral hepatitis. In this study, we used this new model to investigate the role of invariant natural killer T (iNKT) cells during hepacivirus infection in vivo. These cells are enriched in the liver, however their role in viral hepatitis is not well defined. Using high-dimensional flow cytometry and NKT cell deficient mice we analyzed a potential role of iNKT cells in mediating viral clearance, liver pathology or immune-regulation during hepacivirus infection. In addition, we identified new immune-dominant MHC class I restricted viral epitopes and analyzed the impact of iNKT cells on virus-specific CD8+ T cells. We found that rodent hepacivirus infection induced the activation of iNKT cell subsets with a mixed NKT1/NKT2 signature and significant production of type 2 cytokines (IL-4 and IL-13) during acute infection. While iNKT cells were dispensable for viral clearance, the lack of these cells caused higher levels of liver injury during infection. In addition, the absence of iNKT cells resulted in increased effector functions of hepatic antiviral T cells. In conclusion, our study reports a regulatory role of hepatic iNKT cells during hepacivirus infection in vivo. Specifically, our data suggest that iNKT cells skewed towards type 2 immunity limit liver injury during acute infection by mechanisms that include the regulation of effector functions of virus-specific T cells.
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Affiliation(s)
- Svjetlana Raus
- Department of Medicine, Division of Hepatology, and Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, United States
| | - Jarrett Lopez-Scarim
- Department of Medicine, Division of Hepatology, and Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, United States
| | - Joshua Luthy
- BD Life Sciences - FlowJo, Ashland, OR, United States
| | - Eva Billerbeck
- Department of Medicine, Division of Hepatology, and Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, United States
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39
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The unique role of innate lymphoid cells in cancer and the hepatic microenvironment. Cell Mol Immunol 2022; 19:1012-1029. [PMID: 35962192 PMCID: PMC9424527 DOI: 10.1038/s41423-022-00901-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Accepted: 06/22/2022] [Indexed: 11/17/2022] Open
Abstract
Cancer is a complex disease, and despite incredible progress over the last decade, it remains the leading cause of death worldwide. Liver cancers, including hepatocellular carcinoma (HCC), and liver metastases are distinct from other cancers in that they typically emerge as a consequence of long-term low-grade inflammation. Understanding the mechanisms that underpin inflammation-driven tissue remodeling of the hepatic immune environment is likely to provide new insights into much needed treatments for this devastating disease. Group 1 innate lymphoid cells (ILCs), which include natural killer (NK) cells and ILC1s, are particularly enriched in the liver and thought to contribute to the pathogenesis of a number of liver diseases, including cancer. NK cells are an attractive, but underexplored, therapeutic target in hepatic disease due to their role in immunosurveillance and their ability to recognize and eliminate malignant cells. ILC1s are closely related to and share many phenotypic features with NK cells but are less well studied. Thus, their utility in immunotherapeutic approaches is not yet well understood. Here, we review our current understanding of ILCs in cancer with a particular focus on liver and liver-related diseases.
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40
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Mu X, Xiang Z, Xu Y, He J, Lu J, Chen Y, Wang X, Tu CR, Zhang Y, Zhang W, Yin Z, Leung WH, Lau YL, Liu Y, Tu W. Glucose metabolism controls human γδ T-cell-mediated tumor immunosurveillance in diabetes. Cell Mol Immunol 2022; 19:944-956. [PMID: 35821253 PMCID: PMC9338301 DOI: 10.1038/s41423-022-00894-x] [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: 12/20/2021] [Accepted: 06/11/2022] [Indexed: 11/09/2022] Open
Abstract
Patients with type 2 diabetes mellitus (T2DM) have an increased risk of cancer. The effect of glucose metabolism on γδ T cells and their impact on tumor surveillance remain unknown. Here, we showed that high glucose induced Warburg effect type of bioenergetic profile in Vγ9Vδ2 T cells, leading to excessive lactate accumulation, which further inhibited lytic granule secretion by impairing the trafficking of cytolytic machinery to the Vγ9Vδ2 T-cell-tumor synapse by suppressing AMPK activation and resulted in the loss of antitumor activity in vitro, in vivo and in patients. Strikingly, activating the AMPK pathway through glucose control or metformin treatment reversed the metabolic abnormalities and restored the antitumor activity of Vγ9Vδ2 T cells. These results suggest that the impaired antitumor activity of Vγ9Vδ2 T cells induced by dysregulated glucose metabolism may contribute to the increased cancer risk in T2DM patients and that metabolic reprogramming by targeting the AMPK pathway with metformin may improve tumor immunosurveillance.
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Affiliation(s)
- Xiaofeng Mu
- Department of Pediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, PR China
| | - Zheng Xiang
- Department of Pediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, PR China
| | - Yan Xu
- The First Affiliated Hospital, Faculty of Medical Science, Jinan University, Guangzhou, 510632, Guangdong, PR China
- Zhuhai Precision Medical Center, Zhuhai People's Hospital (Zhuhai Hospital Affiliated with Jinan University), Jinan University, Zhuhai, 519000, Guangdong, PR China
- The Biomedical Translational Research Institute, Jinan University, Guangzhou, 510632, Guangdong, PR China
| | - Jing He
- GuangDong 999 Brain Hospital, Guangzhou City, Guangdong Province, PR China
| | - Jianwen Lu
- Department of Endocrinology, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, 510180, PR China
| | - Yuyuan Chen
- The Biomedical Translational Research Institute, Jinan University, Guangzhou, 510632, Guangdong, PR China
| | - Xiwei Wang
- Department of Pediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, PR China
| | - Chloe Ran Tu
- Computational and Systems Biology Interdepartmental Program, University of California, Los Angeles, Los Angeles, CA, 90095, USA
| | - Yanmei Zhang
- Department of Pediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, PR China
| | - Wenyue Zhang
- Department of Pediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, PR China
| | - Zhinan Yin
- Zhuhai Precision Medical Center, Zhuhai People's Hospital (Zhuhai Hospital Affiliated with Jinan University), Jinan University, Zhuhai, 519000, Guangdong, PR China
- The Biomedical Translational Research Institute, Jinan University, Guangzhou, 510632, Guangdong, PR China
| | - Wing-Hang Leung
- Department of Pediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, PR China
| | - Yu-Lung Lau
- Department of Pediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, PR China
| | - Yinping Liu
- Department of Pediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, PR China.
| | - Wenwei Tu
- Department of Pediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, PR China.
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41
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Zhang Y, Tong S, Li S, Wang X, Ren H, Yin W. Increased ILT2 expression contributes to dysfunction of CD56dimCD16+NK cells in chronic hepatitis B virus infection. Antiviral Res 2022; 205:105385. [DOI: 10.1016/j.antiviral.2022.105385] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Revised: 07/10/2022] [Accepted: 07/19/2022] [Indexed: 11/02/2022]
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Ran GH, Lin YQ, Tian L, Zhang T, Yan DM, Yu JH, Deng YC. Natural killer cell homing and trafficking in tissues and tumors: from biology to application. Signal Transduct Target Ther 2022; 7:205. [PMID: 35768424 PMCID: PMC9243142 DOI: 10.1038/s41392-022-01058-z] [Citation(s) in RCA: 121] [Impact Index Per Article: 40.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Revised: 05/24/2022] [Accepted: 06/14/2022] [Indexed: 02/06/2023] Open
Abstract
Natural killer (NK) cells, a subgroup of innate lymphoid cells, act as the first line of defense against cancer. Although some evidence shows that NK cells can develop in secondary lymphoid tissues, NK cells develop mainly in the bone marrow (BM) and egress into the blood circulation when they mature. They then migrate to and settle down in peripheral tissues, though some special subsets home back into the BM or secondary lymphoid organs. Owing to its success in allogeneic adoptive transfer for cancer treatment and its "off-the-shelf" potential, NK cell-based immunotherapy is attracting increasing attention in the treatment of various cancers. However, insufficient infiltration of adoptively transferred NK cells limits clinical utility, especially for solid tumors. Expansion of NK cells or engineered chimeric antigen receptor (CAR) NK cells ex vivo prior to adoptive transfer by using various cytokines alters the profiles of chemokine receptors, which affects the infiltration of transferred NK cells into tumor tissue. Several factors control NK cell trafficking and homing, including cell-intrinsic factors (e.g., transcriptional factors), cell-extrinsic factors (e.g., integrins, selectins, chemokines and their corresponding receptors, signals induced by cytokines, sphingosine-1-phosphate (S1P), etc.), and the cellular microenvironment. Here, we summarize the profiles and mechanisms of NK cell homing and trafficking at steady state and during tumor development, aiming to improve NK cell-based cancer immunotherapy.
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Affiliation(s)
- Guang He Ran
- Department of Immunology, School of Basic Medical, Jiamusi University, 154007, Jiamusi, China
- Institute of Materia Medica, College of Pharmacy, Army Medical University, 400038, Chongqing, China
| | - Yu Qing Lin
- Department of Immunology, School of Basic Medical, Jiamusi University, 154007, Jiamusi, China
- Institute of Materia Medica, College of Pharmacy, Army Medical University, 400038, Chongqing, China
| | - Lei Tian
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA, 91010, USA
| | - Tao Zhang
- Department of Immunology, School of Basic Medical, Jiamusi University, 154007, Jiamusi, China.
| | - Dong Mei Yan
- Department of Immunology, School of Basic Medical, Jiamusi University, 154007, Jiamusi, China.
| | - Jian Hua Yu
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA, 91010, USA.
| | - You Cai Deng
- Institute of Materia Medica, College of Pharmacy, Army Medical University, 400038, Chongqing, China.
- Department of Clinical Hematology, College of Pharmacy, Army Medical University, 400038, Chongqing, China.
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43
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Siegler JJ, Correia MP, Hofman T, Prager I, Birgin E, Rahbari NN, Watzl C, Stojanovic A, Cerwenka A. Human ILC3 Exert TRAIL-Mediated Cytotoxicity Towards Cancer Cells. Front Immunol 2022; 13:742571. [PMID: 35300331 PMCID: PMC8921484 DOI: 10.3389/fimmu.2022.742571] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Accepted: 02/02/2022] [Indexed: 12/29/2022] Open
Abstract
Group 3 helper Innate Lymphoid Cells (ILC3s) are cytokine-producing lymphocytes that respond to stress signals released during disturbed tissue homeostasis and infection. Upon activation, ILC3s secrete IL-22 and IL-17, and orchestrate immune responses against extracellular pathogens. Their role in cancer remains poorly explored. To determine their anti-cancer effector potential, we co-cultured cytokine-activated human ILC3s with cancer cells of different origins. ILC3s were able to directly respond to tumor cells, resulting in enhanced IFN-γ production. Upon tumor cell encounter, ILC3s maintained expression of the transcription factor RORγt, indicating that ILC3s preserved their identity. ILC3s were able to directly kill both hepatocellular carcinoma and melanoma tumor cells expressing cell-death receptor TRAILR2, through the activation of Caspase-8 in target cells. Moreover, liver-derived cytokine-activated ILC3s also expressed TRAIL and were able to eliminate hepatoblastoma cells. Together, our data reveal that ILC3s can participate in anti-tumor immune response through direct recognition of tumor cells resulting in IFN-γ release and TRAIL-dependent cytotoxicity. Thus, ILC3s might be ancillary players of anti-tumor immunity in tissues, acting as primary responders against transformed or metastasizing cells, which might be further exploited for therapies against cancer.
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Affiliation(s)
- Jana-Julia Siegler
- Department of Immunobiochemistry, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.,Mannheim Institute for Innate Immunoscience (MI3), Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | - Margareta P Correia
- Department of Immunobiochemistry, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.,Mannheim Institute for Innate Immunoscience (MI3), Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.,Cancer Biology and Epigenetics Group, Research Center of IPO Porto (CI-IPOP)/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Center (Porto.CCC), Porto, Portugal
| | - Tomáš Hofman
- Department of Immunobiochemistry, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.,Mannheim Institute for Innate Immunoscience (MI3), Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | - Isabel Prager
- Department for Immunology, Leibniz Research Centre for Working Environment and Human Factors at TU Dortmund (IfADo), Dortmund, Germany
| | - Emrullah Birgin
- Department of Surgery, University Clinics Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Nuh N Rahbari
- Department of Surgery, University Clinics Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Carsten Watzl
- Department for Immunology, Leibniz Research Centre for Working Environment and Human Factors at TU Dortmund (IfADo), Dortmund, Germany
| | - Ana Stojanovic
- Department of Immunobiochemistry, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.,Mannheim Institute for Innate Immunoscience (MI3), Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | - Adelheid Cerwenka
- Department of Immunobiochemistry, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.,Mannheim Institute for Innate Immunoscience (MI3), Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.,European Center for Angioscience (ECAS), Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
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44
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Song J, Song H, Wei H, Sun R, Tian Z, Peng H. Requirement of RORα for maintenance and antitumor immunity of liver-resident natural killer cells/ILC1s. Hepatology 2022; 75:1181-1193. [PMID: 34510508 DOI: 10.1002/hep.32147] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2021] [Revised: 08/24/2021] [Accepted: 09/07/2021] [Indexed: 01/19/2023]
Abstract
BACKGROUD AND AIMS Liver type 1 innate lymphoid cells (ILC1s), also known as liver-resident natural killer (LrNK) cells, comprise a high proportion of total hepatic ILCs. However, factors regulating their maintenance and function remain unclear. APPROACH AND RESULTS In this study, we found high expression of retinoid-related orphan nuclear receptor alpha (RORα) in LrNK cells/ILC1s. Mice with conditional ablation of retinoid-related orphan nuclear receptor alpha (Rorα) in LrNK cells/ILC1s and conventional natural killer (cNK) cells had decreased LrNK cells/ILC1s but normal numbers of cNK cells. RORα-deficient LrNK cells/ILC1s displayed increased apoptosis and significantly altered transcriptional profile. Using a murine model of colorectal cancer liver metastasis, we found that RORα conditional deficiency resulted in more aggressive liver tumor progression and impaired effector molecule expression in LrNK cells/ILC1s. Consequently, treatment with the RORα agonist efficiently limited liver metastases and promoted effector molecule expression of LrNK cells/ILC1s. CONCLUSIONS This study reveals a role of RORα in LrNK cell/ILC1 maintenance and function, providing insights into the harnessing of LrNK cell/ILC1 activity in the treatment of liver cancer.
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Affiliation(s)
- Jiaxi Song
- Hefei National Laboratory for Physical Sciences at Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefeiChina
- Institute of ImmunologyUniversity of Science and Technology of ChinaHefeiChina
| | - Hao Song
- Hefei National Laboratory for Physical Sciences at Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefeiChina
- Institute of ImmunologyUniversity of Science and Technology of ChinaHefeiChina
| | - Haiming Wei
- Hefei National Laboratory for Physical Sciences at Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefeiChina
- Institute of ImmunologyUniversity of Science and Technology of ChinaHefeiChina
| | - Rui Sun
- Hefei National Laboratory for Physical Sciences at Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefeiChina
- Institute of ImmunologyUniversity of Science and Technology of ChinaHefeiChina
| | - Zhigang Tian
- Hefei National Laboratory for Physical Sciences at Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefeiChina
- Institute of ImmunologyUniversity of Science and Technology of ChinaHefeiChina
- Research Unit of NK Cell StudyChinese Academy of Medical SciencesHefeiChina
| | - Hui Peng
- Hefei National Laboratory for Physical Sciences at Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefeiChina
- Institute of ImmunologyUniversity of Science and Technology of ChinaHefeiChina
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45
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Abstract
Hepatic macrophages are key immune cells associated with the broad ranges of liver diseases including steatosis, inflammation and fibrosis. Hepatic macrophages interact with other immune cells and orchestrate hepatic immune circumstances. Recently, the heterogenous populations of hepatic macrophages have been discovered termed residential Kupffer cells and monocyte-derived macrophages, and identified their distinct population dynamics during the progression of various liver diseases. Liver injury lead to Kupffer cells activation with induction of inflammatory cytokines and chemokines, which triggers recruitment of inflammatory monocyte-derived macrophages. To understand liver pathology, the functions of different subtypes of liver macrophages should be regarded with different perspectives. In this review, we summarize recent advances in the roles of hepatic macrophages under liver damages and suggest hepatic macrophages as promising therapeutic targets for treating liver diseases.
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Affiliation(s)
- Kyeong-Jin Lee
- Laboratory of Pathology and Physiology, College of Pharmacy, Kangwon National University, Chuncheon 24341, Korea
| | - Mi-Yeon Kim
- Laboratory of Pathology and Physiology, College of Pharmacy, Kangwon National University, Chuncheon 24341, Korea
| | - Yong-Hyun Han
- Laboratory of Pathology and Physiology, College of Pharmacy, Kangwon National University, Chuncheon 24341, Korea
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46
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Tranah TH, Kronsten VT, Shawcross DL. Implications and Management of Cirrhosis-Associated Immune Dysfunction Before and After Liver Transplantation. Liver Transpl 2022; 28:700-716. [PMID: 34738724 DOI: 10.1002/lt.26353] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 10/18/2021] [Accepted: 10/27/2021] [Indexed: 12/28/2022]
Abstract
Cirrhosis-associated immune dysfunction (CAID) describes a panacea of innate and adaptive deficits that result from the sequelae of cirrhotic portal hypertension that is similar in its manifestations regardless of etiology of chronic liver injury. CAID is associated with synchronous observations of dysregulated priming of innate immune effector cells that demonstrate a proinflammatory phenotype but are functionally impaired and unable to adequately prevent invading pathogens. CAID is mainly driven by gut-barrier dysfunction and is associated with deficits of microbial compartmentalization and homeostasis that lead to tonic activation, systemic inflammation, and exhaustion of innate-immune cells. CAID leads to a high frequency of bacterial and fungal infections in patients with cirrhosis that are often associated with acute decompensation of chronic liver disease and acute-on-chronic liver failure and carry a high mortality rate. Understanding the deficits of mucosal and systemic immunity in the context of chronic liver disease is essential to improving care for patients with cirrhosis, preventing precipitants of acute decompensation of cirrhosis, and improving morbidity and survival. In this review, we summarize the detailed dynamic immunological perturbations associated with advanced chronic liver disease and highlight the importance of recognizing immune dysregulation as a sequela of cirrhosis. Furthermore, we address the role of screening, prevention, and early treatment of infections in cirrhosis in improving patient outcomes in transplant and nontransplant settings.
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Affiliation(s)
- Thomas H Tranah
- Institute of Liver Studies, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, London, UK.,Institute of Liver Studies, King's College Hospital National Health Service Foundation Trust, London, UK
| | - Victoria T Kronsten
- Institute of Liver Studies, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, London, UK.,Institute of Liver Studies, King's College Hospital National Health Service Foundation Trust, London, UK
| | - Debbie L Shawcross
- Institute of Liver Studies, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, London, UK.,Institute of Liver Studies, King's College Hospital National Health Service Foundation Trust, London, UK
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47
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Zhang W, Zhao Z, Li F. Natural killer cell dysfunction in cancer and new strategies to utilize NK cell potential for cancer immunotherapy. Mol Immunol 2022; 144:58-70. [DOI: 10.1016/j.molimm.2022.02.015] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Revised: 02/11/2022] [Accepted: 02/15/2022] [Indexed: 12/18/2022]
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48
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Lee KJ, Kim MY, Han YH. Roles of heterogenous hepatic macrophages in the progression of liver diseases. BMB Rep 2022; 55:166-174. [PMID: 35321784 PMCID: PMC9058466] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Revised: 03/02/2022] [Accepted: 03/05/2022] [Indexed: 02/21/2025] Open
Abstract
Hepatic macrophages are key immune cells associated with the broad ranges of liver diseases including steatosis, inflammation and fibrosis. Hepatic macrophages interact with other immune cells and orchestrate hepatic immune circumstances. Recently, the heterogenous populations of hepatic macrophages have been discovered termed residential Kupffer cells and monocyte-derived macrophages, and identified their distinct population dynamics during the progression of various liver diseases. Liver injury lead to Kupffer cells activation with induction of inflammatory cytokines and chemokines, which triggers recruitment of inflammatory monocyte-derived macrophages. To understand liver pathology, the functions of different subtypes of liver macrophages should be regarded with different perspectives. In this review, we summarize recent advances in the roles of hepatic macrophages under liver damages and suggest hepatic macrophages as promising therapeutic targets for treating liver diseases. [BMB Reports 2022; 55(4): 166-174].
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Affiliation(s)
- Kyeong-Jin Lee
- Laboratory of Pathology and Physiology, College of Pharmacy, Kangwon National University, Chuncheon 24341, Korea
| | - Mi-Yeon Kim
- Laboratory of Pathology and Physiology, College of Pharmacy, Kangwon National University, Chuncheon 24341, Korea
| | - Yong-Hyun Han
- Laboratory of Pathology and Physiology, College of Pharmacy, Kangwon National University, Chuncheon 24341, Korea
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49
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Wang Y, Guan Y, Hu Y, Li Y, Lu N, Zhang C. Murine CXCR3+CXCR6+γδT Cells Reside in the Liver and Provide Protection Against HBV Infection. Front Immunol 2022; 12:757379. [PMID: 35126348 PMCID: PMC8814360 DOI: 10.3389/fimmu.2021.757379] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Accepted: 12/28/2021] [Indexed: 11/17/2022] Open
Abstract
Gamma delta (γδ) T cells play a key role in the innate immune response and serve as the first line of defense against infection and tumors. These cells are defined as tissue-resident lymphocytes in skin, lung, and intestinal mucosa. They are also relatively abundant in the liver; however, little is known about the residency of hepatic γδT cells. By comparing the phenotype of murine γδT cells in liver, spleen, thymus, and small intestine, a CXCR3+CXCR6+ γδT-cell subset with tissue-resident characteristics was found in liver tissue from embryos through adults. Liver sinusoidal endothelial cells mediated retention of CXCR3+CXCR6+ γδT cells through the interactions between CXCR3 and CXCR6 and their chemokines. During acute HBV infection, CXCR3+CXCR6+ γδT cells produced high levels of IFN-γ and adoptive transfer of CXCR3+CXCR6+ γδT cells into acute HBV-infected TCRδ−/− mice leading to lower HBsAg and HBeAg expression. It is suggested that liver resident CXCR3+CXCR6+ γδT cells play a protective role during acute HBV infection. Strategies aimed at expanding and activating liver resident CXCR3+CXCR6+ γδT cells both in vivo or in vitro have great prospects for use in immunotherapy that specifically targets acute HBV infection.
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MESH Headings
- Adoptive Transfer/methods
- Animals
- Chemokines/metabolism
- Hepatitis B/metabolism
- Hepatitis B virus/pathogenicity
- Hepatocytes/metabolism
- Hepatocytes/virology
- Intestine, Small/metabolism
- Intestine, Small/virology
- Liver/metabolism
- Liver/virology
- Male
- Mice
- Mice, Inbred BALB C
- Mice, Inbred C57BL
- Mice, Nude
- Receptors, Antigen, T-Cell, gamma-delta/metabolism
- Receptors, CXCR3/metabolism
- Receptors, CXCR6/metabolism
- Spleen/metabolism
- Spleen/virology
- T-Lymphocytes/metabolism
- T-Lymphocytes/virology
- Thymus Gland/metabolism
- Thymus Gland/virology
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Affiliation(s)
- Yanan Wang
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Yun Guan
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China
- Jining No. 1 People’s Hospital, Jining, China
| | - Yuan Hu
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Yan Li
- Institute of Biomedical Sciences, College of Life Sciences, Shandong Normal University, Jinan, China
| | - Nan Lu
- Institute of Diagnostics, School of Medicine, Cheeloo College of Medicine, Shandong University, Jinan, China
- *Correspondence: Cai Zhang, ; Nan Lu,
| | - Cai Zhang
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China
- *Correspondence: Cai Zhang, ; Nan Lu,
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Hirsova P, Bamidele AO, Wang H, Povero D, Revelo XS. Emerging Roles of T Cells in the Pathogenesis of Nonalcoholic Steatohepatitis and Hepatocellular Carcinoma. Front Endocrinol (Lausanne) 2021; 12:760860. [PMID: 34777255 PMCID: PMC8581300 DOI: 10.3389/fendo.2021.760860] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Accepted: 10/14/2021] [Indexed: 12/16/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease worldwide. A significant proportion of patients with NAFLD develop a progressive inflammatory condition termed nonalcoholic steatohepatitis (NASH), which may eventually advance to cirrhosis and hepatocellular carcinoma (HCC). NASH is characterized by steatosis, hepatocyte ballooning, and lobular inflammation. Heightened immune cell infiltration is a hallmark of NASH, yet the mechanisms whereby hepatic inflammation occurs in NASH and how it contributes to disease initiation and progression remain incompletely understood. Emerging evidence indicates that intrahepatic T cell immune mechanisms play an integral role in the pathogenesis of NASH and its transition to HCC. In this review, we summarize the current knowledge regarding the T cell-mediated mechanisms of inflammation in NASH. We highlight recent preclinical and human studies implicating various subsets of conventional and innate-like T cells in the onset and progression of NASH and HCC. Finally, we discuss the potential therapeutic strategies targeting T cell-mediated responses for the treatment of NASH.
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Affiliation(s)
- Petra Hirsova
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, United States
| | - Adebowale O. Bamidele
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, United States
| | - Haiguang Wang
- Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN, United States
| | - Davide Povero
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, United States
| | - Xavier S. Revelo
- Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN, United States
- Center for Immunology, University of Minnesota, Minneapolis, MN, United States
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