Abstract
Ontologically distinct populations of macrophages differentially contribute to organ fibrosis through unknown mechanisms. We applied lineage tracing, single-cell RNA-seq and single molecule fluorescent 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 PDGFA. Using single-cell RNA-seq and spatial transcriptomics in both humans and mice, we identified M-CSFR signaling as one of the novel druggable targets controlling self-maintenance and persistence of these pathogenic monocyte-derived alveolar macrophages. Pharmacological blockade of M-CSFR signaling led to the disappearance of monocyte-derived alveolar macrophages and ameliorated fibrosis. Our findings suggest that inhibition of M-CSFR signaling during fibrosis disrupts an essential fibrotic niche that includes monocyte-derived alveolar macrophages and fibroblasts during asbestos-induced fibrosis.
Footnotes
This manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.
Conflict of interest: Dr. Joshi has nothing to disclose.
Conflict of interest: Dr. Watanabe has nothing to disclose.
Conflict of interest: Dr. Verma has nothing to disclose.
Conflict of interest: Dr. Jablonski has nothing to disclose.
Conflict of interest: Dr. Chen has nothing to disclose.
Conflict of interest: Dr. Cheresh has nothing to disclose.
Conflict of interest: Dr. Markov has nothing to disclose.
Conflict of interest: Dr. Reyfman has nothing to disclose.
Conflict of interest: Dr. McQuattie-Pimentel has nothing to disclose.
Conflict of interest: Dr. Sichizya has nothing to disclose.
Conflict of interest: Dr. Lu has nothing to disclose.
Conflict of interest: Dr. Piseaux has nothing to disclose.
Conflict of interest: Dr. Kirchenbuechler has nothing to disclose.
Conflict of interest: Dr. Flozak has nothing to disclose.
Conflict of interest: Dr. Gottardi has nothing to disclose.
Conflict of interest: Dr. Cuda has nothing to disclose.
Conflict of interest: Dr. Perlman has nothing to disclose.
Conflict of interest: Dr. Jain has nothing to disclose.
Conflict of interest: Dr. Kamp has nothing to disclose.
Conflict of interest: Dr. Misharin has nothing to disclose.
Conflict of interest: Dr. Budinger has nothing to disclose.
This is a PDF-only article. Please click on the PDF link above to read it.
- Received April 1, 2019.
- Accepted September 26, 2019.
- Copyright ©ERS 2019
