老化的骨髓通过助长促纤维化巨噬细胞的持久性而加剧肺纤维化

IF 17.6 1区医学 Q1 IMMUNOLOGY

Science Immunology Pub Date : 2025-03-28 DOI:10.1126/sciimmunol.adk5041

Asma Farhat, Mariem Radhouani, Florian Deckert, Sophie Zahalka, Lisabeth Pimenov, Alina Fokina, Anna Hakobyan, Felicitas Oberndorfer, Jessica Brösamlen, Anastasiya Hladik, Karin Lakovits, Fanzhe Meng, Federica Quattrone, Louis Boon, Cornelia Vesely, Philipp Starkl, Nicole Boucheron, Jörg Menche, Joris van der Veeken, Wilfried Ellmeier, Anna-Dorothea Gorki, Clarissa Campbell, Riem Gawish, Sylvia Knapp

{"title":"老化的骨髓通过助长促纤维化巨噬细胞的持久性而加剧肺纤维化","authors":"Asma Farhat, Mariem Radhouani, Florian Deckert, Sophie Zahalka, Lisabeth Pimenov, Alina Fokina, Anna Hakobyan, Felicitas Oberndorfer, Jessica Brösamlen, Anastasiya Hladik, Karin Lakovits, Fanzhe Meng, Federica Quattrone, Louis Boon, Cornelia Vesely, Philipp Starkl, Nicole Boucheron, Jörg Menche, Joris van der Veeken, Wilfried Ellmeier, Anna-Dorothea Gorki, Clarissa Campbell, Riem Gawish, Sylvia Knapp","doi":"10.1126/sciimmunol.adk5041","DOIUrl":null,"url":null,"abstract":"<div >Pulmonary fibrosis is an incurable disease that manifests with advanced age. Yet, how hematopoietic aging influences immune responses and fibrosis progression remains unclear. Using heterochronic bone marrow transplant mouse models, we found that an aged bone marrow exacerbates lung fibrosis irrespective of lung tissue age. Upon lung injury, there was an increased accumulation of monocyte-derived alveolar macrophages (Mo-AMs) driven by cell-intrinsic hematopoietic aging. These Mo-AMs exhibited an enhanced profibrotic profile and stalled maturation into a homeostatic, tissue-resident phenotype. This delay was shaped by cell-extrinsic environmental signals such as reduced pulmonary interleukin-10 (IL-10), perpetuating a profibrotic macrophage state. We identified regulatory T cells (T<sub>regs</sub>) as critical providers of IL-10 upon lung injury that promote Mo-AM maturation and attenuate fibrosis progression. Our study highlights the impact of an aging bone marrow on lung immune regulation and identifies T<sub>reg</sub>-mediated IL-10 signaling as a promising target to mitigate fibrosis and promote tissue repair.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 105","pages":""},"PeriodicalIF":17.6000,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciimmunol.adk5041","citationCount":"0","resultStr":"{\"title\":\"An aging bone marrow exacerbates lung fibrosis by fueling profibrotic macrophage persistence\",\"authors\":\"Asma Farhat, Mariem Radhouani, Florian Deckert, Sophie Zahalka, Lisabeth Pimenov, Alina Fokina, Anna Hakobyan, Felicitas Oberndorfer, Jessica Brösamlen, Anastasiya Hladik, Karin Lakovits, Fanzhe Meng, Federica Quattrone, Louis Boon, Cornelia Vesely, Philipp Starkl, Nicole Boucheron, Jörg Menche, Joris van der Veeken, Wilfried Ellmeier, Anna-Dorothea Gorki, Clarissa Campbell, Riem Gawish, Sylvia Knapp\",\"doi\":\"10.1126/sciimmunol.adk5041\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div >Pulmonary fibrosis is an incurable disease that manifests with advanced age. Yet, how hematopoietic aging influences immune responses and fibrosis progression remains unclear. Using heterochronic bone marrow transplant mouse models, we found that an aged bone marrow exacerbates lung fibrosis irrespective of lung tissue age. Upon lung injury, there was an increased accumulation of monocyte-derived alveolar macrophages (Mo-AMs) driven by cell-intrinsic hematopoietic aging. These Mo-AMs exhibited an enhanced profibrotic profile and stalled maturation into a homeostatic, tissue-resident phenotype. This delay was shaped by cell-extrinsic environmental signals such as reduced pulmonary interleukin-10 (IL-10), perpetuating a profibrotic macrophage state. We identified regulatory T cells (T<sub>regs</sub>) as critical providers of IL-10 upon lung injury that promote Mo-AM maturation and attenuate fibrosis progression. Our study highlights the impact of an aging bone marrow on lung immune regulation and identifies T<sub>reg</sub>-mediated IL-10 signaling as a promising target to mitigate fibrosis and promote tissue repair.</div>\",\"PeriodicalId\":21734,\"journal\":{\"name\":\"Science Immunology\",\"volume\":\"10 105\",\"pages\":\"\"},\"PeriodicalIF\":17.6000,\"publicationDate\":\"2025-03-28\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.science.org/doi/reader/10.1126/sciimmunol.adk5041\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Science Immunology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.science.org/doi/10.1126/sciimmunol.adk5041\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"IMMUNOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Science Immunology","FirstCategoryId":"3","ListUrlMain":"https://www.science.org/doi/10.1126/sciimmunol.adk5041","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"IMMUNOLOGY","Score":null,"Total":0}

引用次数: 0

摘要

肺纤维化是一种不治之症，表现为老年。然而，造血老化如何影响免疫反应和纤维化进展仍不清楚。使用异慢性骨髓移植小鼠模型，我们发现与肺组织年龄无关的衰老骨髓加剧了肺纤维化。肺损伤后，单核细胞来源的肺泡巨噬细胞（Mo-AMs）的积累增加，这是由细胞固有的造血老化驱动的。这些mo - am表现出增强的纤维化特征，并停滞成熟为稳态的组织常驻表型。这种延迟是由细胞外源性环境信号形成的，如肺白细胞介素-10 （IL-10）减少，使巨噬细胞的纤维化状态永久化。我们发现调节性T细胞（T regs）是肺损伤时IL-10的关键提供者，促进Mo-AM成熟和减轻纤维化进展。我们的研究强调了衰老骨髓对肺免疫调节的影响，并确定了T reg介导的IL-10信号作为减轻纤维化和促进组织修复的有希望的靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

An aging bone marrow exacerbates lung fibrosis by fueling profibrotic macrophage persistence

查看原文本刊更多论文

An aging bone marrow exacerbates lung fibrosis by fueling profibrotic macrophage persistence

Pulmonary fibrosis is an incurable disease that manifests with advanced age. Yet, how hematopoietic aging influences immune responses and fibrosis progression remains unclear. Using heterochronic bone marrow transplant mouse models, we found that an aged bone marrow exacerbates lung fibrosis irrespective of lung tissue age. Upon lung injury, there was an increased accumulation of monocyte-derived alveolar macrophages (Mo-AMs) driven by cell-intrinsic hematopoietic aging. These Mo-AMs exhibited an enhanced profibrotic profile and stalled maturation into a homeostatic, tissue-resident phenotype. This delay was shaped by cell-extrinsic environmental signals such as reduced pulmonary interleukin-10 (IL-10), perpetuating a profibrotic macrophage state. We identified regulatory T cells (T_regs) as critical providers of IL-10 upon lung injury that promote Mo-AM maturation and attenuate fibrosis progression. Our study highlights the impact of an aging bone marrow on lung immune regulation and identifies T_reg-mediated IL-10 signaling as a promising target to mitigate fibrosis and promote tissue repair.

求助全文

通过发布文献求助，成功后即可免费获取论文全文。去求助

来源期刊

Science Immunology Immunology and Microbiology-Immunology

CiteScore

32.90

自引率

2.00%

发文量

183

期刊介绍： Science Immunology is a peer-reviewed journal that publishes original research articles in the field of immunology. The journal encourages the submission of research findings from all areas of immunology, including studies on innate and adaptive immunity, immune cell development and differentiation, immunogenomics, systems immunology, structural immunology, antigen presentation, immunometabolism, and mucosal immunology. Additionally, the journal covers research on immune contributions to health and disease, such as host defense, inflammation, cancer immunology, autoimmunity, allergy, transplantation, and immunodeficiency. Science Immunology maintains the same high-quality standard as other journals in the Science family and aims to facilitate understanding of the immune system by showcasing innovative advances in immunology research from all organisms and model systems, including humans.