纤维化
巨噬细胞
肺纤维化
肺泡巨噬细胞
生物
细胞生物学
免疫学
单核细胞
肺
病理
医学
内科学
生物化学
体外
作者
Nikita Joshi,Satoshi Watanabe,Rohan Verma,Renea Jablonski,Ching-I Chen,Paul Cheresh,Nikolay S. Markov,Paul A. Reyfman,Alexandra C. McQuattie‐Pimentel,Lango Sichizya,Ziyan Lu,Raul Piseaux‐Aillon,David Kirchenbüechler,Annette S. Flozak,Cara J. Gottardi,Carla M. Cuda,Harris Perlman,Manu Jain,David W. Kamp,G. R. Scott Budinger,Alexander V. Misharin
出处
期刊:The European respiratory journal
[European Respiratory Society]
日期:2019-10-10
卷期号:55 (1): 1900646-1900646
被引量:185
标识
DOI:10.1183/13993003.00646-2019
摘要
Ontologically distinct populations of macrophages differentially contribute to organ fibrosis through unknown mechanisms. We applied lineage tracing, single-cell RNA sequencing and single-molecule fluorescence in situ hybridisation to a spatially restricted model of asbestos-induced pulmonary fibrosis. We demonstrate that tissue-resident alveolar macrophages, tissue-resident peribronchial and perivascular interstitial macrophages, and monocyte-derived alveolar macrophages are present in the fibrotic niche. Deletion of monocyte-derived alveolar macrophages but not tissue-resident alveolar macrophages ameliorated asbestos-induced lung fibrosis. Monocyte-derived alveolar macrophages were specifically localised to fibrotic regions in the proximity of fibroblasts where they expressed molecules known to drive fibroblast proliferation, including platelet-derived growth factor subunit A. Using single-cell RNA sequencing and spatial transcriptomics in both humans and mice, we identified macrophage colony-stimulating factor receptor (M-CSFR) signalling as one of the novel druggable targets controlling self-maintenance and persistence of these pathogenic monocyte-derived alveolar macrophages. Pharmacological blockade of M-CSFR signalling led to the disappearance of monocyte-derived alveolar macrophages and ameliorated fibrosis. Our findings suggest that inhibition of M-CSFR signalling during fibrosis disrupts an essential fibrotic niche that includes monocyte-derived alveolar macrophages and fibroblasts during asbestos-induced fibrosis.
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