IL10 trains macrophage profibrotic function after lung injury

Abstract

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 <i>Pdgfa</i> in bleomycin-induced lung fibrosis in mice. Deletion of <i>Pdgfa</i> with <i>Cx3cr1-CreERT2</i> decreased bleomycin-induced lung fibrosis. Among a panel of in vitro macrophage polarizing stimuli, robust induction of <i>Pdgfa</i> was noted with IL10 in both mouse and human moMacs. Likewise, analysis of single-cell data revealed high expression of the receptor <i>IL10RA</i> in moMacs from human fibrotic lungs. Studies with <i>IL10-GFP</i> mice revealed that IL10-expressing cells were increased after injury in mice and colocalized with moMacs. Notably, deletion of <i>IL10ra</i> with <i>Csf1r-Cre: IL10ra fl/fl</i> mice decreased both <i>Pdgfa</i> 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.