Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Department of Pharmaceutical Biochemistry, Kumamoto University Faculty of Life Sciences, Kumamoto, Japan.
JCI Insight. 2018 Aug 9;3(15). doi: 10.1172/jci.insight.121175.
Epithelial cells are the first line of defense against external dangers, and contribute to induction of adaptive immunity including Th17 responses. However, it is unclear whether specific epithelial signaling pathways are essential for the development of robust IL-17-mediated immune responses. In mice, the development of psoriatic inflammation induced by imiquimod required keratinocyte TRAF6. Conditional deletion of TRAF6 in keratinocytes abrogated dendritic cell activation, IL-23 production, and IL-17 production by γδ T cells at the imiquimod-treated sites. In contrast, hapten-induced contact hypersensitivity and papain-induced IgE production were not affected by loss of TRAF6. Loss of psoriatic inflammation was not solely due to defective imiquimod sensing, as subcutaneous administration of IL-23 restored IL-17 production but did not reconstitute psoriatic pathology in the mutant animals. Thus, TRAF6 was required for the full development of IL-17-mediated inflammation. Therefore, epithelial TRAF6 signaling plays an essential role in both triggering and propagating IL-17-mediated psoriatic inflammation.
上皮细胞是抵御外部危险的第一道防线，有助于诱导适应性免疫，包括 Th17 反应。然而，目前尚不清楚特定的上皮信号通路对于产生强大的 IL-17 介导的免疫反应是否至关重要。在小鼠中，咪喹莫特诱导的银屑病炎症的发展需要角质形成细胞 TRAF6。角质形成细胞中 TRAF6 的条件性缺失消除了树突状细胞的激活、IL-23 的产生以及 γδ T 细胞在咪喹莫特处理部位产生的 IL-17。相比之下，变应原诱导的接触超敏反应和木瓜蛋白酶诱导的 IgE 产生不受 TRAF6 缺失的影响。银屑病炎症的缺失并非仅仅是由于咪喹莫特感应缺陷所致，因为 IL-23 的皮下给药恢复了 IL-17 的产生，但并未在突变动物中重建银屑病病理学。因此，TRAF6 对于 IL-17 介导的炎症的完全发展是必需的。因此，上皮 TRAF6 信号传导在触发和传播 IL-17 介导的银屑病炎症中发挥着重要作用。
