IL-33 Mediates IL-17A-induced REG3A To Regulate Wound Healing And Host Defense Against S.aureus Infection In Skin

Skin is the first line to protect hosts against environmental stimuli. After skin injury, skin wounds usually get microbial infection if they don’t receive careful management. Although appropriate inflammatory responses are necessary for wound repair, excessive inflammatory responses lead to delayed wound healing or tissue necrosis. Therefore, it is urgent to investigate the process of wound healing and increase host defenses against microbial infection in wounds.Our previous studies have found that IL-17A induces the expression of REG3A in keratinocytes, and REG3A feeds back on keratinocyte to inhibit terminal differentiation, thus promoting wound healing. However, little is known about the specific molecular mechanism by which IL-17A regulates the expression of REG3A.To explore the molecular mechansim by which IL-17A induces REG3A expres-sion, we first treated keratinocytes with recombinant IL-17A and found that except for IL-17RA, Actl, p38 and β-catenin all participated in the induction of REG3A as silencing of IL17RA, Act1 and β-catenin or inhibiton of p38 MAPK by its inhibitor SB202190 significantly decreased IL-17A-induced REG3A expression. Furthermore, the induction of REG3 A by IL-17A was dependent on IL-33, a member of IL-1 family as IL33 silengcing completely abrogated the expression of REG3A by IL-17A. Morevoer, the induction of REG3 A by IL-33 depended on its receptor ST2, followed by the activation of JNK-AKT-STAT3 signaling pathway. Taken together, IL-17A/ IL-33/REG3Aplays a critical role in promoting wound healing after skin injury.In addition to promoting tissue repair, REG3A has been reported as an antibacterial protein to inhibit the growth of pathogenic microorganisms in the gastrointestinal tract. Hundreds of millions of microorganisms inhabit on human skin and most of these microbia have benigh relationship with hosts. However, once these microbes breach the skin barrier, they will cause skin infectious disease. How REG3 A plays a role in skin infections remains unknown.We found that REG3A, RegⅢγ and cell lysates of keratinocytes treated with IL-33 could inhibit the growth of Staphylococcus aureus in vitro. In vivo experiment further proved that IL-33 induced RegⅢγ to inhibit S. aureus infection in mouse skin, and IL-17 A could regulate both of them during infection.Taken together, our study has for the first time shown that the IL-17A/IL-33/ REG3A in keratinocytes plays an important role in promoting wound healing and inhibiting S. aureus skin infection. These findings provide new insights into important roles of keratinocytes in tissue repair, and potential therapeutic strategies for the treatment of skin wounds and bacterial infection.