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Abstract：
Psoriasis is characterized by keratinocyte (KC) hyperproliferation and inflammatory cell infiltration, but the mechanisms remain unclear. In an imiquimod-induced mouse psoriasiform model, p38 activity is significantly elevated in KCs and p38α specific deletion in KCs ameliorates skin inflammation. p38α signaling promotes KC proliferation and psoriasis-related proinflammatory gene expression during psoriasis development. Mechanistically, p38α enhances KC proliferation and production of inflammatory cytokines and chemokines by activating STAT3. While p38α signaling in KCs does not affect the expression of IL-23 and IL-17, it substantially amplifies the IL-23/IL-17 pathogenic axis in psoriasis. The therapeutic effect of IL-17 neutralization is associated with decreased p38 and STAT3 activities in KCs and targeting the p38α-STAT3 axis in KCs ameliorates the severity of psoriasis. As IL-17 also highly activates p38 and STAT3 in KCs, our findings reveal a sustained signaling circuit important for psoriasis development, highlighting p38α-STAT3 axis as an important target for psoriasis treatment.
摘要：
银屑病的特征是角质形成细胞（KC）过度增殖和炎症细胞浸润，但机制尚不清楚。在咪喹莫特诱导的小鼠银屑病模型中，KC中p38活性显著升高，KC中p38α特异性缺失可改善皮肤炎症。p38α信号在银屑病发展过程中促进KC增殖和银屑病相关促炎基因表达。机械上,p38α通过激活STAT3增强KC增殖和炎性细胞因子和趋化因子的产生。虽然KC中的p38α信号传导不影响IL-23和IL-17的表达，但它实质上放大了牛皮癣中的IL-23/IL-17致病轴。IL-17中和的治疗效果与KC中p38和STAT3活性降低有关，靶向KC中的p38α-STAT3轴可改善牛皮癣的严重程度。由于IL-17也高度激活KCs中的p38和STAT3，我们的发现揭示了一个持续的信号回路对银屑病的发展很重要，突出p38α-STAT3轴作为银屑病治疗的重要靶点。
