Joshi, N; Watanabe, S; Verma, R; Jablonski, RP; Chen, CI; Cheresh, P; Markov, NS; Reyfman, PA; Mcquattie-Pimentel, AC; Sichizya, L; Lu, Z; Piseaux-Aillon, R; Kirchenbuechler, D; Flozak, AS; Gottardi, CJ; Cuda, CM; Perlman, H; Jain, M; Kamp, DW; Budinger, GRS; Misharin, AV
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.
Cardiovascular System & Cardiology; Respiratory System; Research &; Experimental Medicine; crocidolite asbestos, fetal monocytes, mouse lung, expression, resident,; cells, rats