Lipopeptide 78 from <i>Staphylococcus epidermidis</i> Activates β-Catenin To Inhibit Skin Inflammation

Abstract

The appropriate inflammatory response is essential for normal wound repair, and skin commensal <i>Staphylococcus epidermidis</i> has been shown to regulate TLR3-mediated inflammatory response to maintain skin homeostasis after injury. However, the underlying mechanism by which <i>S. epidermidis</i> regulates wound-induced inflammation remains largely unexplored. In this study we identified a previously unknown lipopeptide 78 (LP78) from <i>S. epidermidis</i> and showed that LP78 inhibited TLR3-mediated skin inflammation to promote wound healing. Skin injury activated TLR3/NF-κB to promote the interaction of p65 and PPARγ in nuclei and then initiated the inflammatory response in keratinocytes. LP78 activated TLR2-SRC to induce β-catenin phosphorylation at Tyr⁶⁵⁴ The phospho-β-catenin translocated into nuclei to bind to PPARγ, thus disrupting the interaction between p65 and PPARγ. The disassociation between p65 and PPARγ reduced the expression of TLR3-induced inflammatory cytokines in skin wounds of normal and diabetic mice, which correlated with accelerated wound healing. Our data demonstrate that <i>S. epidermidis</i>-derived LP78 inhibits skin inflammation to promote wound healing and suggest that LP78 might be a potential compound for the treatment of delayed or unhealed wounds.