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

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.

• Authors: Nikita Joshi, Satoshi Watanabe, Rohan Verma, Renea P Jablonski, Ching-I Chen, Paul Cheresh, Nikolay S Markov, Paul A Reyfman, Alexandra C McQuattie-Pimentel, Lango Sichizya, Ziyan Lu, Raul Piseaux-Aillon, David Kirchenbuechler, Annette S Flozak, Cara J Gottardi, Carla M Cuda, Harris Perlman, Manu Jain, David W Kamp, G R Scott Budinger, Alexander V Misharin
• Journal: The European respiratory journal (Eur Respir J) Vol. 55 Issue 1 (01 2020) ISSN: 1399-3003 [Electronic] England
• PMID: 31601718 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright ©ERS 2020.

Chemical References

• Macrophage Colony-Stimulating Factor
• Receptor, Macrophage Colony-Stimulating Factor

Topics

• Animals
• Fibrosis
• Humans
• Macrophage Colony-Stimulating Factor
• Macrophages (pathology)
• Macrophages, Alveolar
• Mice
• Monocytes
• Pulmonary Fibrosis (chemically induced, pathology)
• Receptor, Macrophage Colony-Stimulating Factor