926 Innate antiviral immunity is activated upon skin injury via an IL-27/STAT1 axis

Abstract

Activation of antimicrobial immunity is critical to control infection following skin injury. While the induction of antibacterial host defense molecules is relatively well-defined, regulation of antiviral proteins (AVPs) in the skin is largely unknown. Here, we show that AVPs are potently induced following acute traumatic skin injury in an IL-27-STAT1-dependent manner. Using human skin organ cultures and murine wound models, we discovered that excisional punch biopsy-induced wounding triggers production of multiple AVPs, including OAS1, OAS2, and OASL (p < 0.05). Since we previously reported that IL-27 plays a functional role in skin wound repair, we hypothesized that IL-27 may stimulate AVP expression in the skin. Indeed, IL-27 induced OAS2 both in vitro in human keratinocytes and in vivo upon s.c injection into mouse skin (p < 0.01) in a dose- and time-dependent manner. Addition of IL-27 neutralizing AB to wounds or genetic KO of the Il27 receptor significantly decreased OAS2 (p < 0.01), suggesting that IL-27 plays a critical role in injury-induced production of OAS2. IL-27 also suppresses viral infection in human keratinocytes and enhances dsRNA-induced AVP expression (p < 0.01) supporting the functional relevance of IL-27 in antiviral immunity. Using an siRNA screening approach, we demonstrate that OAS2 upregulation in response to IL-27 was IFNAR1-, TLR3-, MDA5-, MAVS-, RIGi-, TRAF6-, IkBe-, TBK1- and JAK1-independent, but STAT1- and IRF3-dependent (p < 0.001). In further support of this pathway, IL-27 was shown to cause rapid and transient nuclear translocation of p-STAT1 and IRF3, and IL-27 failed to induce OAS2 in a STAT1KO keratinocyte cell line. Together, our data suggest that IL-27 promotes skin antiviral competence through activation of AVPs upon cutaneous injury. New knowledge of the regulatory pathways of AVP induction following injury will aid in our understanding of cutaneous innate immunity and skin repair.