Interleukin-10-mediated regenerative postnatal tissue repair is dependent on regulation of hyaluronan metabolism via fibroblast-specific STAT3 signaling

The cytokine IL-10 has potent antifibrotic effects in models of adult fibrosis, but themechanisms of action are unclear. Here, we report a novel finding that IL-10 triggers a signal transducer and activator of transcription 3 (STAT3)-dependent signaling pathway that regulates hyaluronan (HA) metabolism and drives adult fibroblasts to synthesize an HA-rich pericellular matrix, which mimics the fetal regenerative wound healing phenotype with reduced fibrosis. By using cre-lox-mediated novel, inducible, fibroblast-, keratinocyte-, and wound-specific STAT3- knockdown postnatalmice-plus syngeneic fibroblast cell-Transplantmodels-we demonstrate that the regenerative effects of IL-10 in postnatal wounds are dependent on HA synthesis and fibroblast-specific STAT3-dependent signaling. The importance of IL-10-inducedHAsynthesis for regenerativewound healing is demonstrated by inhibition of HA synthesis in a murine wound model by administering 4-methylumbelliferone. Although IL-10 and STAT3 signalingwere intact, the antifibrotic repair phenotype that is induced by IL-10 overexpressionwas abrogated in this model. Our data show a novel role for IL-10 beyond its accepted immune-regulatorymechanism. The opportunity for IL-10 to regulate a fibroblast-specific formation of a regenerative,HA-rich wound extracellularmatrixmay lead to the developmentof innovative therapies to attenuatepostnatal fibrosis inorgansystemsordiseases inwhichdysregulated inflammation andHAintersect.