期刊
EUROPEAN RESPIRATORY JOURNAL
卷 55, 期 1, 页码 -出版社
EUROPEAN RESPIRATORY SOC JOURNALS LTD
DOI: 10.1183/13993003.00646-2019
关键词
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资金
- MSD Life Science Foundation
- Public Interest Incorporated Foundation, Japan
- Northwestern University's Lung Sciences Training Program [5T32HL076139-13, 1F32HL136111-01A1]
- NIH [AR064546, HL134375, AG049665, UH2AR067687, HL143800, ES013995, HL071643, HL135124, AI135964]
- United States-Israel Binational Science Foundation [2013247]
- Rheumatology Research Foundation [05/06/14]
- Veterans Administration grant [BX000201]
- Veterans Affairs Merit Award [2IO1BX000786-05A2]
- Dept of Defense grant [PR141319]
- David W. Cugell and Christina Enroth-Cugell Fellowship Program at Northwestern University
- US Dept of Defense grant [PR141319]
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.
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