SIL-36R Inhibits IL-17/ IL-36γ-induced REG3A To Delay Wound Healing

Keratinocytes locate in the outermost layer of the skin, constituting 90% of cells found in epidermis. They play important roles in wound healing and the pathogenesis of psoriasis.It has been reported that IL-17 promotes wound healing, and induces IL-36y and REG3A in keratinocytes, however, the underlying mechanism is unclear. In our study,we show that IL-17 induced IL-36y expression via the activation of IL-17RA and Actl. Moreover, IL-17 induced REG3A expression partially dependent on IL-36y as IL-36y sliencing decreased IL-17-induced REG3A expression in keratinocytes.REG3A and IL-36y were highly expressed in keratinocytes which in the skin wound and the lesion sites of psoriasis. But the regulatory mechanisms between REG3A and IL-36y is unclear. We treated keratinocytes with IL-36y, and found that IL-36y induced REG3A expression in keratinocytes via the activation of IL-36 receptor followed by the activation of p38-Akt-p-catenin signal pathway.In vivo, we found that the rate of wound healing was decreased in IL-17 knock out mice, compared with wild type mice, along with the decreased expression of IL-36y and RegⅢγin the wounds of IL-17 knockout mice. Intradermal injection of IL-36y into the dorsa skin of IL-17 knock-out mice induced the expression of RegⅢγ and promoted the wound healing.Furthermore, we found a soluble IL-36 receptor, sIL-36R.. Overexpression of sIL-36R in keratinocytes inhibited IL-17 and IL-36y-induced REG3A expression and cell proliferation. According to other soluble receptors in IL-1 family, we speculated that sIL-36R may prevent IL-36y from binding with IL-36 receptor and attenuate IL-36y signal pathway, thus delaying wound healing.Taken together, our study has demonstrated that IL-17 promotes wound healing through activation of IL-36y and REG3A. Meanwhile, sIL-36R can inhibit the function of IL-36y. Our study provides a new theoretical basis for accelerating wound healing.