Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, China.
Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Commun Biol. 2024 Aug 15;7(1):999. doi: 10.1038/s42003-024-06700-w.
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.
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 中的 p38 活性显著升高，而 KC 中 p38α 的特异性缺失可改善皮肤炎症。在银屑病发展过程中，p38α 信号通过激活 STAT3 促进 KC 增殖和银屑病相关促炎基因的表达。在机制上，p38α 通过激活 STAT3 增强 KC 的增殖和炎症细胞因子和趋化因子的产生。虽然 KC 中的 p38α 信号不影响 IL-23 和 IL-17 的表达，但它在银屑病中显著放大了 IL-23/IL-17 致病轴。IL-17 中和的治疗效果与 KC 中 p38 和 STAT3 活性的降低有关，靶向 KC 中的 p38α-STAT3 轴可改善银屑病的严重程度。由于 IL-17 也能高度激活 KC 中的 p38 和 STAT3，我们的发现揭示了一个对银屑病发展很重要的持续信号通路，突出了 p38α-STAT3 轴作为银屑病治疗的一个重要靶点。
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