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

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 BudingerAlexander V. Misharin

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
JournalThe European respiratory journal
Volume55
Issue number1
DOIs
StatePublished - Jan 1 2020

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine

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    Joshi, N., Watanabe, S., Verma, R., Jablonski, R. P., Chen, C. I., Cheresh, P., Markov, N. S., Reyfman, P. A., McQuattie-Pimentel, A. C., Sichizya, L., Lu, Z., Piseaux-Aillon, R., Kirchenbuechler, D., Flozak, A. S., Gottardi, C. J., Cuda, C. M., Perlman, H., Jain, M., Kamp, D. W., ... Misharin, A. V. (2020). A spatially restricted fibrotic niche in pulmonary fibrosis is sustained by M-CSF/M-CSFR signalling in monocyte-derived alveolar macrophages. The European respiratory journal, 55(1). https://doi.org/10.1183/13993003.00646-2019