嘌呤受体P2Y6调控IL-17/AKT介导的皮肤炎症及银屑病发生的机制研究

Psoriasis is a chronic recurrent inflammatory skin disease in a multi-gene genetic background. However, little is known about the role of the G-protein coupled receptor family, including purinergic receptors, in psoriasis. Our previous study found that the expression of purinergic receptor P2Y6 was significantly increased in human psoriatic lesions. Interestingly,in the imiquimod-induced mouse psoriasis model, P2Y6-deficient mice were found to have more severe psoriasis, and P2Y6 ligand UDP-treated mice reduced imiquimod-induced psoriasis-like lesions. This story will focus on the regulation of P2Y6 and its molecular mechanism in the pathogenesis of psoriasis. The main strategy is to study the regulation function of the key inflammatory factor IL-17/AKT in the pathogenesis of psoriasis. Imiquimod and IL-23 induced psoriasis mouse model and P2Y6-/- mouse and UDP treatment model and through in vitro cell experiments, RNA-seq and proteome To analyze and further explore the regulation of P2Y6 on IL-17/AKT-induced skin inflammation in keratinocytes, and to explore the mechanism of P2Y6 regulating IL-17A/AKT in the pathogenesis of psoriasis, and provides a theoretical basis for the clinical treatment of psoriasis for UDP.

银屑病是一种多基因遗传背景下的慢性复发性炎症性皮肤病，但对于包括嘌呤受体在内的G蛋白偶联受体家族在银屑病中的作用，知之甚少。我们前期研究发现P2Y6在人银屑病皮损中是高表达的。而有趣的是，在咪喹莫特诱导小鼠银屑病模型中，发现P2Y6缺失小鼠，银屑病更为严重，而且P2Y6配体UDP处理的小鼠可以减轻咪喹莫特诱导的银屑病样皮损Z本课题将着重探讨银屑病发病过程中P2Y6的调控作用及其分子机制，主要策略是以对银屑病发病过程中的关键性通路IL-17/AKT的调节功能作为研究切入点，通过咪喹莫特及IL-23诱导的银屑病小鼠模型以及P2Y6-/-小鼠，P2Y6配体UDP处理模型等体内模型以及体外细胞实验，RNA-seq及蛋白质组学分析，深入探索P2Y6对IL-17/AKT诱导的皮肤炎症的调控作用，探究P2Y6调节IL-17A/AKT在银屑病发病中的作用机制，为UDP用于银屑病临床治疗提供理论依据。

银屑病是一种常见的皮肤病，其特征是角质形成细胞增殖和免疫细胞浸润。尿苷二磷酸（UDP）及其受体P2ry6已被确定与炎症反应密切相关，但P2ry6在牛皮癣中的作用尚不清楚。在这里，我们证明了P2ry6表达在人和小鼠银屑病皮肤中上调。P2ry6缺失加重IMQ诱导的银屑病样病变和表皮增生，局部应用UDP可有效缓解。更重要的是，我们提供的证据表明，在IMQ微环境中的P2ry6缺陷皮肤中的IL-17A / AKT / STAT3信号传导有助于异常角质形成细胞增殖，中性粒细胞浸润和促炎细胞因子释放。此外，我们发现P2ry6与IL-17A/PI3K/AKT/STAT3轴之间存在负反馈环路，以抵抗由于P2ry6对PTEN的正向调节而导致的银屑病样病变的快速发展。这些数据表明，P2ry6在预防银屑病发病机制中起着重要的保护作用，因此可能是银屑病治疗的有吸引力的靶点。

内容获取失败，请点击重试