Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine, Shanghai Institute of Immunology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
Xin Hua Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China.
Sci Signal. 2018 Mar 13;11(521):eaao1685. doi: 10.1126/scisignal.aao1685.
Dendritic cells (DCs) contribute to psoriasis pathogenesis. In a mouse model of imiquimod-induced psoriasiform skin inflammation, we found that p38α activity in Langerhans cells (LCs), a skin-resident subset of DCs, promoted the generation of T cells that produce IL-17, a proinflammatory cytokine that is implicated in autoimmune disease. Deletion of p38α in LCs, but not in other skin or circulating DC subsets or T cells, decreased T cell-mediated psoriasiform skin inflammation in mice. The activity of p38α in LCs specifically promoted IL-17 production from γδ and CD4 T cells by increasing the abundance of IL-23 and IL-6, two cytokines that stimulate IL-17 secretion. Inhibition of p38 activity through either pharmacological inhibition or genetic deletion also reduced the severity of established psoriasiform skin inflammation. Together, our findings indicate a critical role for p38α signaling in LCs in promoting inflammatory responses in the skin and suggest that targeting p38α signaling in LCs may offer an effective therapeutic approach to treat psoriasis.
树突状细胞 (DCs) 参与银屑病发病机制。在咪喹莫特诱导的银屑病样皮肤炎症的小鼠模型中，我们发现朗格汉斯细胞 (LCs) 中的 p38α 活性促进了产生白细胞介素 17 (IL-17) 的 T 细胞的产生，IL-17 是一种与自身免疫性疾病有关的促炎细胞因子。在 LCs 中而不是在其他皮肤或循环 DC 亚群或 T 细胞中删除 p38α 可减少小鼠的 T 细胞介导的银屑病样皮肤炎症。LCs 中的 p38α 活性通过增加刺激 IL-17 分泌的两种细胞因子 IL-23 和 IL-6 的丰度，特异性促进 γδ 和 CD4 T 细胞产生 IL-17。通过药理学抑制或基因缺失抑制 p38 活性也降低了已建立的银屑病样皮肤炎症的严重程度。总之，我们的研究结果表明 p38α 信号在 LCs 中在促进皮肤炎症反应中具有关键作用，并表明靶向 LCs 中的 p38α 信号可能为治疗银屑病提供一种有效的治疗方法。
