Owen P. Martin, Michael S. Wallace, Christopher Oetheimer, Hailey B. Patel, Michael D. Butler, Lai Ping Wong, Pinzhu Huang, Joshua Elbaz, Charlotte Costentin, Shadi Salloum, Zoe Reinus, Adaeze Obinelo, Ulandt Kim, Stuti Shroff, Kathleen E. Corey, Yury V. Popov, Edgar D. Charles, Ruslan I. Sadreyev, Raymond T. Chung, Nadia Alatrakchi
{"title":"人类肝脏和血液免疫细胞在脂肪肝疾病阶段的单细胞图谱揭示了与肝功能障碍和纤维化有关的独特特征","authors":"Owen P. Martin, Michael S. Wallace, Christopher Oetheimer, Hailey B. Patel, Michael D. Butler, Lai Ping Wong, Pinzhu Huang, Joshua Elbaz, Charlotte Costentin, Shadi Salloum, Zoe Reinus, Adaeze Obinelo, Ulandt Kim, Stuti Shroff, Kathleen E. Corey, Yury V. Popov, Edgar D. Charles, Ruslan I. Sadreyev, Raymond T. Chung, Nadia Alatrakchi","doi":"10.1038/s41590-025-02255-y","DOIUrl":null,"url":null,"abstract":"Immune cells play a central yet poorly understood role in metabolic dysfunction-associated steatotic liver disease and metabolic dysfunction-associated steatohepatitis (MASLD/MASH), a global cause of liver disease with limited treatment. Limited access to human livers and lack of studies across MASLD/MASH stages thwart identification of stage-specific immunological targets. Here we provide a unique single-cell RNA sequencing atlas of paired peripheral blood and liver fine-needle aspirates from a full-spectrum MASLD/MASH human cohort. Our findings included heightened immunoregulatory programs with MASH progression, such as enriched hepatic regulatory T cells, monocytic myeloid-derived suppressor cells, TREM2+S100A9+ macrophages and S100hiHLAlo type 2 conventional dendritic cells. Hepatic cytotoxic T cell functions increased with inflammation, but decreased with fibrosis, while acquiring an exhausted signature, whereas natural killer cell-driven toxicity intensified. Our dataset proposes immunological mechanisms for increased fibrogenesis and vulnerability to liver cancer and infections in MASH and provides a basis for a deeper understanding of human immunological dysfunction in chronic liver disease and a roadmap to new targeted therapies. Alatrakchi and colleagues profile immune cells from liver and blood obtained from patients with MASLD/MASH using single-cell sequencing. They note increased immunoregulatory programs that correlated with increased fibrogenesis and disease progression.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"26 9","pages":"1596-1611"},"PeriodicalIF":27.6000,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Single-cell atlas of human liver and blood immune cells across fatty liver disease stages reveals distinct signatures linked to liver dysfunction and fibrogenesis\",\"authors\":\"Owen P. Martin, Michael S. Wallace, Christopher Oetheimer, Hailey B. Patel, Michael D. Butler, Lai Ping Wong, Pinzhu Huang, Joshua Elbaz, Charlotte Costentin, Shadi Salloum, Zoe Reinus, Adaeze Obinelo, Ulandt Kim, Stuti Shroff, Kathleen E. Corey, Yury V. Popov, Edgar D. Charles, Ruslan I. Sadreyev, Raymond T. Chung, Nadia Alatrakchi\",\"doi\":\"10.1038/s41590-025-02255-y\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"Immune cells play a central yet poorly understood role in metabolic dysfunction-associated steatotic liver disease and metabolic dysfunction-associated steatohepatitis (MASLD/MASH), a global cause of liver disease with limited treatment. Limited access to human livers and lack of studies across MASLD/MASH stages thwart identification of stage-specific immunological targets. Here we provide a unique single-cell RNA sequencing atlas of paired peripheral blood and liver fine-needle aspirates from a full-spectrum MASLD/MASH human cohort. Our findings included heightened immunoregulatory programs with MASH progression, such as enriched hepatic regulatory T cells, monocytic myeloid-derived suppressor cells, TREM2+S100A9+ macrophages and S100hiHLAlo type 2 conventional dendritic cells. Hepatic cytotoxic T cell functions increased with inflammation, but decreased with fibrosis, while acquiring an exhausted signature, whereas natural killer cell-driven toxicity intensified. Our dataset proposes immunological mechanisms for increased fibrogenesis and vulnerability to liver cancer and infections in MASH and provides a basis for a deeper understanding of human immunological dysfunction in chronic liver disease and a roadmap to new targeted therapies. Alatrakchi and colleagues profile immune cells from liver and blood obtained from patients with MASLD/MASH using single-cell sequencing. 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Single-cell atlas of human liver and blood immune cells across fatty liver disease stages reveals distinct signatures linked to liver dysfunction and fibrogenesis
Immune cells play a central yet poorly understood role in metabolic dysfunction-associated steatotic liver disease and metabolic dysfunction-associated steatohepatitis (MASLD/MASH), a global cause of liver disease with limited treatment. Limited access to human livers and lack of studies across MASLD/MASH stages thwart identification of stage-specific immunological targets. Here we provide a unique single-cell RNA sequencing atlas of paired peripheral blood and liver fine-needle aspirates from a full-spectrum MASLD/MASH human cohort. Our findings included heightened immunoregulatory programs with MASH progression, such as enriched hepatic regulatory T cells, monocytic myeloid-derived suppressor cells, TREM2+S100A9+ macrophages and S100hiHLAlo type 2 conventional dendritic cells. Hepatic cytotoxic T cell functions increased with inflammation, but decreased with fibrosis, while acquiring an exhausted signature, whereas natural killer cell-driven toxicity intensified. Our dataset proposes immunological mechanisms for increased fibrogenesis and vulnerability to liver cancer and infections in MASH and provides a basis for a deeper understanding of human immunological dysfunction in chronic liver disease and a roadmap to new targeted therapies. Alatrakchi and colleagues profile immune cells from liver and blood obtained from patients with MASLD/MASH using single-cell sequencing. They note increased immunoregulatory programs that correlated with increased fibrogenesis and disease progression.
期刊介绍:
Nature Immunology is a monthly journal that publishes the highest quality research in all areas of immunology. The editorial decisions are made by a team of full-time professional editors. The journal prioritizes work that provides translational and/or fundamental insight into the workings of the immune system. It covers a wide range of topics including innate immunity and inflammation, development, immune receptors, signaling and apoptosis, antigen presentation, gene regulation and recombination, cellular and systemic immunity, vaccines, immune tolerance, autoimmunity, tumor immunology, and microbial immunopathology. In addition to publishing significant original research, Nature Immunology also includes comments, News and Views, research highlights, matters arising from readers, and reviews of the literature. The journal serves as a major conduit of top-quality information for the immunology community.