Superoxide dismutase 3 inhibits LL-37/KLK-5-mediated skin inflammation through modulation of EGFR and associated inflammatory cascades.
Abstract The expressions of LL-37 and KLK-5 were found to be altered in various dermatoses, including atopic dermatitis, psoriasis, and rosacea. However, the downstream inflammatory effect of LL-37 and KLK-5 is not as well-studied. In addition, there is little high-quality evidence for the treatment of LL-37- and KLK-5-mediated inflammation. In this study, we investigated the effect of SOD3 on LL-37- or KLK-5-induced skin inflammation in vitro and in vivo, and its underlying anti-inflammatory mechanisms. Our data showed that SOD3 significantly reduced both LL-37- and KLK-5-induced expression of pro-inflammatory mediators and suppressed the activation of EGFR, PAR2, NLRP3, and p38/ERK signaling pathways in human keratinocytes. Moreover, SOD3 suppressed LL-37-induced expression of inflammatory mediators, ROS production and p38/ERK activation in mast cells. In addition, subcutaneous injection of KLK-5 in SOD3 knock-out (KO) mice exhibited erythema with increased epidermal thickness, mast cell and neutrophil infiltration, expression of inflammatory mediators and activation of EGFR, PAR2, NLRP3, and downstream MAP kinase pathways. However, treatment with SOD3 in SOD3 KO mice rescued KLK-5-induced inflammatory cascades. Similarly, KLK-5-induced inflammations in wild-type mice were also ameliorated when treated with SOD3. Taken together, our data suggest that SOD3 is a potentially effective therapy for both LL-37-and KLK-5-induced skin inflammation.