A spatially restricted fibrotic niche in pulmonary fibrosis is sustained by M-CSF/M-CSFR signalling in monocyte-derived alveolar macrophages

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 · 发表于：European Respiratory Journal · 年份：2019 · DOI：10.1183/13993003.00646-2019 · 被引用次数：345 · 研究领域：Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis、Occupational and environmental lung diseases、IL-33, ST2, and ILC Pathways

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.