Journal
AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY
Volume 322, Issue 3, Pages L495-L502Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajplung.00458.2021
Keywords
IL10; lung injury; macrophages; Pdgfa; tissue fibrosis
Categories
Funding
- National Institutes of Health (NIH), University of California, San Francisco-Gladstone Institute of Virology & Immunology Center for AIDS Research [P30-AI027763]
- NIH [R01 AI150449]
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This study reveals the involvement of CX3CR1+ monocyte-derived macrophages (moMacs) in bleomycin-induced lung fibrosis through the production of Pdgfa. Analysis at the single-cell level shows high expression of the receptor IL10-RA in moMacs from human fibrotic lungs. Furthermore, a novel IL10-dependent mechanism of macrophage polarization is identified.
Cx3cr1+ monocyte-derived macrophages (moMacs) are recruited to tissues after injury and are known to have profibrotic effects, but the cell-cell interactions and specific pathways that regulate this polarization and function are incompletely understood. Here we investigate the role of moMac-derived Pdgfa in bleomycin-induced lung fibrosis in mice. Deletion of Pdgfa with Cx3cr1-CreERT2 decreased bleomycin-induced lung fibrosis. Among a panel of in vitro macrophage polarizing stimuli, robust induction of Pdgfa was noted with 100 in both mouse and human moMacs. Likewise, analysis of single-cell data revealed high expression of the receptor IL10-RA in moMacs from human fibrotic lungs. Studies with IL10-GFP mice revealed that 100-expressing cells were increased after injury in mice and colocalized with moMacs. Notably, deletion of IL10ra with Csflr-Cre: IL10ra mice decreased both Pdgfa expression in moMacs and lung fibrosis. Taken together, these findings reveal a novel, IL10-dependent mechanism of macrophage polarization leading to fibroblast activation after injury.
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