Cx3cr1+ monocyte-derived macrophages (moMacs) are recruited to tissues after injury and are known to have pro-fibrotic 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 vitromacrophage polarizing stimuli, robust induction of Pdgfa was noted with IL10 in both mouse and human moMacs. Likewise, analysis of single cell data revealed high expression of the receptor IL10RA in moMacs from human fibrotic lungs. Studies with IL10-GFP mice revealed that IL10-expressing cells were increased after injury in mice and co-localized with moMacs. Notably, deletion of IL10ra with Csf1r-Cre : IL10ra fl/fl 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.

Keywords: Fibrosis; IL10; Macrophage; Pdgfa.