Laboratory of Dermato-Immunology, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
Department of Reconstructive Sciences, Center for Regenerative Medicine and Skeletal Development, Institute for Systems Genomics, University of Connecticut, Farmington, Connecticut, USA.
J Invest Dermatol. 2020 Mar;140(3):656-665.e8. doi: 10.1016/j.jid.2019.08.434. Epub 2019 Aug 26.
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 superoxide dismutase 3 (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, protease-activated receptor 2, nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3, and p38/extracellular signal-regulated kinase signaling pathways in human keratinocytes. Moreover, SOD3 suppressed LL-37-induced expression of inflammatory mediators, reactive oxygen species production, and p38/extracellular signal-regulated kinase activation in mast cells. In addition, subcutaneous injection of KLK-5 in SOD3 knockout mice exhibited erythema with increased epidermal thickness, mast cell and neutrophil infiltration, expression of inflammatory mediators, and activation of EGFR, protease-activated receptor 2, nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3, and downstream mitogen-activated protein kinase pathways. However, treatment with SOD3 in SOD3 knockout mice rescued KLK-5-induced inflammatory cascades. Similarly, KLK-5-induced inflammation in wild-type mice was 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.
LL-37 和 KLK-5 的表达在各种皮肤病中被发现发生改变，包括特应性皮炎、银屑病和酒渣鼻。然而，LL-37 和 KLK-5 的下游炎症效应尚未得到充分研究。此外，针对 LL-37 和 KLK-5 介导的炎症的治疗方法，证据质量也较低。在这项研究中，我们研究了超氧化物歧化酶 3（SOD3）对 LL-37 或 KLK-5 诱导的皮肤炎症的体外和体内作用及其潜在的抗炎机制。我们的数据表明，SOD3 显著降低了 LL-37 和 KLK-5 诱导的促炎介质的表达，并抑制了人类角质形成细胞中 EGFR、蛋白酶激活受体 2、核苷酸结合域、富含亮氨酸的家族、富含吡喃结构域的 3 和 p38/细胞外信号调节激酶信号通路的激活。此外，SOD3 抑制了 LL-37 诱导的肥大细胞中炎症介质的表达、活性氧的产生和 p38/细胞外信号调节激酶的激活。此外，KLK-5 在 SOD3 基因敲除小鼠中的皮下注射表现出红斑，伴有表皮厚度增加、肥大细胞和中性粒细胞浸润、炎症介质的表达和 EGFR、蛋白酶激活受体 2、核苷酸结合域、富含亮氨酸的家族、富含吡喃结构域的 3 和下游丝裂原激活蛋白激酶途径的激活。然而，在 SOD3 基因敲除小鼠中用 SOD3 治疗挽救了 KLK-5 诱导的炎症级联反应。同样，当用 SOD3 治疗时，KLK-5 诱导的野生型小鼠的炎症也得到了改善。总之，我们的数据表明 SOD3 可能是治疗 LL-37 和 KLK-5 诱导的皮肤炎症的有效方法。
