Single-cell Profiling of Intrahepatic Immune Cells Reveals an Expansion of Tissue-resident Cytotoxic CD4+ T Lymphocyte Subset Associated With Pathogenesis of Alcoholic-associated Liver DiseasesSummary
Background & Aims: The immunological mechanisms underpinning the pathogenesis of alcoholic-associated liver disease (ALD) remain incompletely elucidated. This study aims to explore the transcriptomic profiles of hepatic immune cells in ALD compared with healthy individuals and those with met...
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Elsevier
2025-01-01
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| Series: | Cellular and Molecular Gastroenterology and Hepatology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352345X24001668 |
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| author | Chao Gao Shiguan Wang Xiaoyu Xie Pierluigi Ramadori Xinying Li Xiaoyu Liu Xue Ding Jinyuan Liang Bowen Xu Yawei Feng Xueying Tan Haoran Wang Yan Zhang Haiyan Zhang Tingguo Zhang Ping Mi Shiyang Li Cuijuan Zhang Detian Yuan Mathias Heikenwalder Peng Zhang |
| author_facet | Chao Gao Shiguan Wang Xiaoyu Xie Pierluigi Ramadori Xinying Li Xiaoyu Liu Xue Ding Jinyuan Liang Bowen Xu Yawei Feng Xueying Tan Haoran Wang Yan Zhang Haiyan Zhang Tingguo Zhang Ping Mi Shiyang Li Cuijuan Zhang Detian Yuan Mathias Heikenwalder Peng Zhang |
| author_sort | Chao Gao |
| collection | DOAJ |
| description | Background & Aims: The immunological mechanisms underpinning the pathogenesis of alcoholic-associated liver disease (ALD) remain incompletely elucidated. This study aims to explore the transcriptomic profiles of hepatic immune cells in ALD compared with healthy individuals and those with metabolic dysfunction-associated steatotic liver disease (MASLD). Methods: We utilized single-cell RNA sequencing to analyze liver samples from healthy subjects and patients with MASLD and ALD, focusing on the immune cell landscapes within the liver. Key alterations in immune cell subsets were further validated using liver biopsy samples from additional patient cohorts. Results: We observed a significant accumulation of CD4+ T cells in livers of patients with ALD, surpassing the prevalence of CD8+ T cells, in contrast to patients with MASLD and healthy counterparts, whereas natural killer (NK) cells and γδT cells exhibited reduced intrahepatic infiltration. In-depth transcriptional and developmental trajectory analyses unveiled that a distinct CD4+ subset characterized by granzyme K (GZMK) expression, displaying a tissue-resident signature and terminal effector state, prominently enriched among CD4+ T cells infiltrating the livers of patients with ALD. Subsequent examination of an independent ALD patient cohort corroborated the substantial enrichment of GZMK+CD4+ T lymphocytes, primarily within liver fibrotic zones, suggesting their potential involvement in disease progression. Additionally, we noted shifts in myeloid populations, with expanded APOE+ macrophage and FCGR3B+ monocyte subsets in ALD samples relative to MASLD and healthy tissues. Conclusions: In summary, this study unravels the intricate cellular diversity within hepatic immune cell populations, highlighting the pivotal immune pathogenic role of the GZMK+CD4+ T lymphocyte subset in ALD pathogenesis. |
| format | Article |
| id | doaj-art-545f05d68d42451f8a811744a7281e81 |
| institution | Kabale University |
| issn | 2352-345X |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cellular and Molecular Gastroenterology and Hepatology |
| spelling | doaj-art-545f05d68d42451f8a811744a7281e812025-01-17T04:49:35ZengElsevierCellular and Molecular Gastroenterology and Hepatology2352-345X2025-01-01192101411Single-cell Profiling of Intrahepatic Immune Cells Reveals an Expansion of Tissue-resident Cytotoxic CD4+ T Lymphocyte Subset Associated With Pathogenesis of Alcoholic-associated Liver DiseasesSummaryChao Gao0Shiguan Wang1Xiaoyu Xie2Pierluigi Ramadori3Xinying Li4Xiaoyu Liu5Xue Ding6Jinyuan Liang7Bowen Xu8Yawei Feng9Xueying Tan10Haoran Wang11Yan Zhang12Haiyan Zhang13Tingguo Zhang14Ping Mi15Shiyang Li16Cuijuan Zhang17Detian Yuan18Mathias Heikenwalder19Peng Zhang20Department of Hepatobiliary Surgery, General Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, ChinaDepartment of Clinical Laboratory, Qilu Hospital of Shandong University, Jinan, Shandong, China; Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, ChinaDepartment of Gastroenterology, Qilu Hospital of Shandong University, Jinan, Shandong, ChinaDivision of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany; University Tuebingen, Faculty of Medicine, Institute for Interdisciplinary Research on Cancer Metabolism and Chronic Inflammation, M3-Research Center for Malignome, Metabolome and Microbiome, Tübingen, GermanyDepartment of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, ChinaAdvanced Medical Research Institute, Shandong University, Jinan, Shandong, ChinaDepartment of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, ChinaDepartment of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, ChinaDepartment of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, ChinaDepartment of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, ChinaDepartment of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, ChinaDepartment of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, ChinaDepartment of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, ChinaDepartment of Biochemistry, Heze Medical College, Heze, Shandong, ChinaInstitute of Pathology and Pathophysiology, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, ChinaDepartment of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, ChinaAdvanced Medical Research Institute, Shandong University, Jinan, Shandong, ChinaInstitute of Pathology and Pathophysiology, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China; Department of Pathology, Qilu Hospital of Shandong University, Jinan, Shandong, China; Correspondence Address correspondence to: Cuijuan Zhang, Institute of Pathology and Pathophysiology, Cheeloo College of Medicine, Shandong University, Jinan 250012, China.Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China; Detian Yuan, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, China.Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany; University Tuebingen, Faculty of Medicine, Institute for Interdisciplinary Research on Cancer Metabolism and Chronic Inflammation, M3-Research Center for Malignome, Metabolome and Microbiome, Tübingen, Germany; Mathias Heikenwalder, University Tuebingen, Faculty of Medicine, Institute for Interdisciplinary Research on Cancer Metabolism and Chronic Inflammation, M3-Research Center for Malignome, Metabolome and Microbiome, Otfried-Müller-Straße 37, 72076 Tübingen, Germany.Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China; Peng Zhang, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, China.Background & Aims: The immunological mechanisms underpinning the pathogenesis of alcoholic-associated liver disease (ALD) remain incompletely elucidated. This study aims to explore the transcriptomic profiles of hepatic immune cells in ALD compared with healthy individuals and those with metabolic dysfunction-associated steatotic liver disease (MASLD). Methods: We utilized single-cell RNA sequencing to analyze liver samples from healthy subjects and patients with MASLD and ALD, focusing on the immune cell landscapes within the liver. Key alterations in immune cell subsets were further validated using liver biopsy samples from additional patient cohorts. Results: We observed a significant accumulation of CD4+ T cells in livers of patients with ALD, surpassing the prevalence of CD8+ T cells, in contrast to patients with MASLD and healthy counterparts, whereas natural killer (NK) cells and γδT cells exhibited reduced intrahepatic infiltration. In-depth transcriptional and developmental trajectory analyses unveiled that a distinct CD4+ subset characterized by granzyme K (GZMK) expression, displaying a tissue-resident signature and terminal effector state, prominently enriched among CD4+ T cells infiltrating the livers of patients with ALD. Subsequent examination of an independent ALD patient cohort corroborated the substantial enrichment of GZMK+CD4+ T lymphocytes, primarily within liver fibrotic zones, suggesting their potential involvement in disease progression. Additionally, we noted shifts in myeloid populations, with expanded APOE+ macrophage and FCGR3B+ monocyte subsets in ALD samples relative to MASLD and healthy tissues. Conclusions: In summary, this study unravels the intricate cellular diversity within hepatic immune cell populations, highlighting the pivotal immune pathogenic role of the GZMK+CD4+ T lymphocyte subset in ALD pathogenesis.http://www.sciencedirect.com/science/article/pii/S2352345X24001668Alcoholic-associated Liver DiseaseCD4+ T LymphocyteGranzyme KMetabolic Dysfunction-associated Steatotic Liver DiseaseSingle-cell RNA Sequencing |
| spellingShingle | Chao Gao Shiguan Wang Xiaoyu Xie Pierluigi Ramadori Xinying Li Xiaoyu Liu Xue Ding Jinyuan Liang Bowen Xu Yawei Feng Xueying Tan Haoran Wang Yan Zhang Haiyan Zhang Tingguo Zhang Ping Mi Shiyang Li Cuijuan Zhang Detian Yuan Mathias Heikenwalder Peng Zhang Single-cell Profiling of Intrahepatic Immune Cells Reveals an Expansion of Tissue-resident Cytotoxic CD4+ T Lymphocyte Subset Associated With Pathogenesis of Alcoholic-associated Liver DiseasesSummary Cellular and Molecular Gastroenterology and Hepatology Alcoholic-associated Liver Disease CD4+ T Lymphocyte Granzyme K Metabolic Dysfunction-associated Steatotic Liver Disease Single-cell RNA Sequencing |
| title | Single-cell Profiling of Intrahepatic Immune Cells Reveals an Expansion of Tissue-resident Cytotoxic CD4+ T Lymphocyte Subset Associated With Pathogenesis of Alcoholic-associated Liver DiseasesSummary |
| title_full | Single-cell Profiling of Intrahepatic Immune Cells Reveals an Expansion of Tissue-resident Cytotoxic CD4+ T Lymphocyte Subset Associated With Pathogenesis of Alcoholic-associated Liver DiseasesSummary |
| title_fullStr | Single-cell Profiling of Intrahepatic Immune Cells Reveals an Expansion of Tissue-resident Cytotoxic CD4+ T Lymphocyte Subset Associated With Pathogenesis of Alcoholic-associated Liver DiseasesSummary |
| title_full_unstemmed | Single-cell Profiling of Intrahepatic Immune Cells Reveals an Expansion of Tissue-resident Cytotoxic CD4+ T Lymphocyte Subset Associated With Pathogenesis of Alcoholic-associated Liver DiseasesSummary |
| title_short | Single-cell Profiling of Intrahepatic Immune Cells Reveals an Expansion of Tissue-resident Cytotoxic CD4+ T Lymphocyte Subset Associated With Pathogenesis of Alcoholic-associated Liver DiseasesSummary |
| title_sort | single cell profiling of intrahepatic immune cells reveals an expansion of tissue resident cytotoxic cd4 t lymphocyte subset associated with pathogenesis of alcoholic associated liver diseasessummary |
| topic | Alcoholic-associated Liver Disease CD4+ T Lymphocyte Granzyme K Metabolic Dysfunction-associated Steatotic Liver Disease Single-cell RNA Sequencing |
| url | http://www.sciencedirect.com/science/article/pii/S2352345X24001668 |
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