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Cited by 344Interstitial Lung Diseases and Idiopathic Pulmonary FibrosisOccupational and environmental lung diseasesChronic Obstructive Pulmonary Disease (COPD) Research

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

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Joshi, Nikita, Watanabe, Satoshi, Verma, Rohan, Jablonski, Renea P., Chen, Ching-I, Cheresh, Paul, Markov, Nikolay S., Reyfman, Paul A. +13 more·2020·European Respiratory Journal
DOI 10.1183/13993003.00646-2019PMC PMC6962769

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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.

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  • The pathogenic role of Mo-AMs in lung fibrosis is largely attributed to their production of pro-fibrotic mediators such as TGF-β, PDGF-α, osteopontin, and MMPs.

    “The pathogenic role of Mo-AMs in lung fibrosis has been largely attributed to their activity in producing a number of pro-fibrotic mediators, such as TGF-β, PDGF-α, osteopontin (OPN), and MMPs1,3,11,13,15,18,28.”

    From TREM2 promotes lung fibrosis via controlling alveolar macrophage survival and pro-fibrotic activity (2025) · cites this paper as [13]

    The Results section on single-cell RNA sequencing identifies Spp1 (osteopontin), Mmp12, and Mmp14 among pro-fibrotic genes enriched in the Mo-AM-associated AM3 cluster. The Results section on fibroblast activation also reports Pdgfa expression in Mo-AMs. But the paper lists Tgfb1 with the generic genes of AM1 and AM2, not AM3, and its gene-expression findings do not establish production of all four mediators by Mo-AMs. Page numbers are unavailable in our copy. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Only Mo-AMs, not the entire type of cells, are responsible for the detrimental role of lung macrophages in pulmonary fibrosis.

    “Recent studies have made inroads into this challenge by demonstrating that it is only a subgroup, the Mo-AMs, and not the entire type of cells, that are responsible for the detrimental role of lung macrophages in pulmonary fibrosis1,3,10,13.”

    From TREM2 promotes lung fibrosis via controlling alveolar macrophage survival and pro-fibrotic activity (2025) · cites this paper as [13]

    The Results (no page provided) show that deleting monocyte-derived alveolar macrophages attenuated asbestos-induced fibrosis in mice, whereas depleting tissue-resident alveolar macrophages did not. This supports a harmful role for the Mo-AM subgroup rather than all alveolar macrophages in that model. The claim extends the finding to pulmonary fibrosis generally and implies that no other lung macrophage subgroup contributes; the Discussion leaves open a possible role for interstitial macrophages in regulating monocytes. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Mo-AMs, but not TR-AMs, are responsible for the pro-fibrotic activity of lung macrophages.

    “Mo-AMs, but not TR-AMs, are responsible for the pro-fibrotic activity of this group of cells1,3,10,13”

    From TREM2 promotes lung fibrosis via controlling alveolar macrophage survival and pro-fibrotic activity (2025) · cites this paper as [13]

  • Depletion of Mo-AMs confers protection from lung fibrosis in multiple mouse models.

    “depletion of Mo-AMs via several strategies conferred protection from lung fibrosis in multiple mouse models1,3,10,11,13,20”

    From TREM2 promotes lung fibrosis via controlling alveolar macrophage survival and pro-fibrotic activity (2025) · cites this paper as [13]

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Cited by

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Authors
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., Budinger, G. R. S., & Misharin, A. V.
Affiliations
  • Northwestern University (US)
  • Kanazawa University (JP)
Corresponding author
Misharin, Alexander V.
ORCID
Venue
European Respiratory Journal
Publisher
European Respiratory Society (ERS)
Published
2019-10-10
Volume
55
Issue
1
Pages
1900646
ISSN
  • 0903-1936 (ISSN-L)
  • 1399-3003
DOI
10.1183/13993003.00646-2019
PMC
PMC6962769
OpenAlex
W2979837800
Cited by
344
References
15
Citations by year
2026: 54 · 2025: 60 · 2024: 62 · 2023: 44 · 2022: 49 · 2021: 43 · 2020: 28 · 2019: 3
FWCI
22.61
Type
journal article
Language
en
Open access
Licence
Locations
  • European Respiratory Journal (publishedVersion, cc-by-nc)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
Funders
  • National Institute on Aging (AG049665)
  • National Heart, Lung, and Blood Institute (HL135124)
  • The Veterans Administration (BX000201)
  • National Institute of Allergy and Infectious Diseases (AI135964)
  • U.S. Department of Defense (PR141319)
Topics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Occupational and environmental lung diseases
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Chronic Obstructive Pulmonary Disease (COPD) Research
Keywords
pulmonary fibrosis, fibrotic niche, interstitial macrophages, fibroblast proliferation, PDGF-A, spatial transcriptomics
MeSH terms
Animals, Fibrosis, Humans, Macrophages, Monocytes, Pulmonary Fibrosis, Macrophage Colony-Stimulating Factor, Receptor, Macrophage Colony-Stimulating Factor, Macrophages, Alveolar, Mice

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