KLK6 expression in skin induces PAR1-mediated psoriasiform dermatitis and inflammatory joint disease

Kallikrein-related peptidase 6 (KLK6) is a secreted serine protease hypothesized to promote inflammation via cleavage of protease-activated receptors (PAR)1 and PAR2. KLK6 levels are elevated in multiple inflammatory and autoimmune conditions, but no definitive role in pathogenesis has been established. Here, we show that skin-targeted overexpression of KLK6 causes generalized, severe psoriasiform dermatitis with spontaneous development of debilitating psoriatic arthritis-like joint disease. The psoriatic skin and joint phenotypes are reversed by normalization of skin KLK6 levels and attenuated following genetic elimination of PAR1 but not PAR2. Conservation of this regulatory pathway was confirmed in human psoriasis using vorapaxar, an FDA-approved PAR1 antagonist, on explanted lesional skin from psoriasis patients. Beyond defining a critical role for KLK6-PAR1 signaling in promoting psoriasis, our results demonstrate that KLK6-PAR1-mediated inflammation in the skin alone is sufficient to drive inflammatory joint disease. Further, we identify PAR1 as a promising cytokine-independent target in therapy of psoriasis and psoriatic arthritis. RNA-seq was performed to identify genes with altered expression in skin from Klk6+ transgenic mice (n = 3 males, n = 2 females) as compared to WT mice (n = 3 males, n = 2 females).

激肽释放酶相关肽酶6（Kallikrein-related peptidase 6, KLK6）是一种分泌型丝氨酸蛋白酶，被推测可通过切割蛋白酶激活受体1（protease-activated receptor 1, PAR1）与蛋白酶激活受体2（protease-activated receptor 2, PAR2）促进炎症反应。KLK6水平在多种炎症性与自身免疫性疾病中均存在升高，但其在疾病发病机制中的确切作用尚未得到明确证实。本研究证实，皮肤靶向过表达KLK6可引发全身性重症银屑病样皮炎，并自发形成衰弱性银屑病关节炎样关节病变。皮肤与关节的银屑病样表型可通过恢复皮肤KLK6水平得到逆转，且可通过遗传敲除PAR1（而非PAR2）得以缓解。利用沃拉帕沙（vorapaxar）——一种获美国食品药品监督管理局（Food and Drug Administration, FDA）批准的PAR1拮抗剂——处理银屑病患者的皮损外植体，证实了该调控通路在人类银屑病中具有保守性。本研究不仅明确了KLK6-PAR1信号通路在银屑病发生发展中的关键作用，还证实仅皮肤内KLK6-PAR1介导的炎症反应即可独立驱动炎性关节病变。此外，本研究鉴定出PAR1可作为治疗银屑病与银屑病关节炎的极具潜力的非细胞因子依赖性治疗靶点。本研究对Klk6过表达转基因小鼠（n=3只雄性、n=2只雌性）与野生型（Wild Type, WT）小鼠（n=3只雄性、n=2只雌性）的皮肤组织进行了RNA测序（RNA-seq），以筛选表达水平发生显著改变的基因。