A spatially restricted fibrotic niche in pulmonary fibrosis is sustained by M-CSF/M-CSFR signalling in monocyte-derived alveolar macrophages. Issue 1 (16th January 2020)

• Record Type: Journal Article
• Authors: Joshi, Nikita; Watanabe, Satoshi; Verma, Rohan; Jablonski, Renea P.; Chen, Ching-I; Cheresh, Paul; Markov, Nikolay S.; Reyfman, Paul A.; McQuattie-Pimentel, Alexandra C.; Sichizya, Lango; Lu, Ziyan; Piseaux-Aillon, Raul; Kirchenbuechler, David; Flozak, Annette S.; Gottardi, Cara J.; Cuda, Carla M.; Perlman, Harris; Jain, Manu; Kamp, David W.; Budinger, G.R. Scott; Misharin, Alexander V.
• Is Part Of: European respiratory journal. Volume 55:Issue 1(2020)
• Publication Date: 2020-01-16
• Subjects: Respiratory organs -- Diseases -- Periodicals; Respiration -- Periodicals; 616.2
• DOI: 10.1183/13993003.00646-2019
• Languages: English
• ISSNs: 0903-1936

Abstract

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. Monocyte-derived alveolar macrophages orchestrate the development of the fibrotic niche, causally related to fibrosis and maintained via M-CSF/M-CSFR signalling http://bit.ly/2nDjS20