直接阻断IL-17A/TNF-α信号能有效治疗中重度银屑病，但这种方式存在局限性能引发多种药物副作用。精确调控IL-17A/TNF-α信号下致病通路的药物设计是解决问题的关键。我们首次发现激活表皮角质形成细胞中的ERK1/2能有效抑制IL-17A/TNF-α炎症信号。我们还发现小分子Destruxin A5能细胞特异性地活化表皮角质形成细胞中的ERK1/2，在不影响具有重要生理功能的NF-κB通路的情况下抑制IL-17A/TNF-α炎症信号。本课题将评价Destruxin A5对IL-17A/TNF-α诱导的炎症分子抑制情况；利用DARTS等方法寻找Destruxin A5的靶蛋白；利用免疫共沉淀等方法阐明ERK1/2被调控的方式；利用免疫组化和组织免疫荧光评价Destruxin A5治疗小鼠银屑病的效果。本研究将为实现精确调控IL-17A/TNF-α炎症信号而治疗银屑病的目标提供新思路。

Direct blocking the IL-17A/TNF-α signaling can be effective in the treatment of moderate-to-severe psoriasis, but it will bring many drug side-effects such as destruction of the basic immunity, indicating that there exist limitations. A smart drug design that can precisely control the IL-17A/TNF-α signaling by avoiding inhibition of the important physiological pathways under this signal is a clever way to solve this problem. We first proved that activation of ERK1/2 in epidermal keratinocytes can effectively inhibit IL-17A/TNF-α inflammation signaling. Additionally, we found Destruxin A5, a small molecule, which specifically activates ERK1/2 in the epidermal keratinocytes and inhibits the IL-17A/TNF-α inflammation signaling without affecting the NF-κB pathway that has important physiological functions. In this study, the genome-wide transcriptional analysis was used to evaluate the regulation of IL-17A/TNF-α inflammation signaling by Destruxin A5-activated ERK1/2. The target protein of Destruxin A5 was detected by DARTS method, CESTA method and SPR-Biacore method. Western blotting, immunoprecipitation and SPR-Biacore were used to elucidate the effect of Destruxin A5 on ERK1/2 phosphorylation. The effect of Destruxin A5 on psoriasis was evaluated by immunohistochemistry and tissue immunofluorescence. This study will provide a new way to precisely regulate the IL-17A/TNF-α signaling and treat psoriasis.