Unprocessed IL-36a co-operates with IL-1 in psoriasiform skin inflammation (CAM1P.148)

Abstract

Psoriasis has been linked to overzealous IL-1 and IL-36 signaling; however, whether these cytokines have redundant, interrelated or independent functions have not been examined. It is also unknown if the IL-36 cytokines undergo processing in vivo. Here, we examined IL-36 expression, functional involvement and interaction with IL-1/IL-1R1 signaling in a mouse model of drug induced psoriasiform skin inflammation. Normal skin did not express detectable levels of IL-36a, IL-36b, or IL-36g protein. All 3 cytokine mRNAs were up-regulated during inflammation; however, only IL-36a secretion could be detected in explant skin cultures. Significantly less (25%, p<0.01) was released from IL-1R1 deficient skin. This demonstrates that IL-1 regulates IL-36a expression in vivo. Interestingly, the released IL-36a was not processed. Using knockout (KO) mice for each individual IL-36 cytokine, we found that IL-36a, but not IL-36b and IL-36g, significantly contributed to pathology. Specifically, we observed thinner epidermis and decreased dermal inflammation in IL-36a KO mice compared to wild type. Treated IL-36a/IL-1R1 double KO mice exhibited even thinner epidermal and dermal thickness. Neutrophil recruitment to the epidermis was impaired in the IL-36a KO mice, but could be rescued with application of the chemokine CXCL1. In summary, we conclude that IL-1 dispatches unprocessed IL-36a, which in turn boosts the pro-inflammatory activity of IL-1 signaling during psoriasis-like skin inflammation.