溶血磷脂酸（LPA）通过LPAR5/PKD1信号通路作用角质形成细胞促进银屑病的分子机制研究

LPA及受体有着广泛的生物学功能，然而在银屑病中的作用尚未阐明。预实验结果表明LPA receptor5（LPAR5）在银屑病皮损中高表达，其LPA丰度在银屑病小鼠血浆、皮损及银屑病患者血浆中显著增高，并能够作用于角质形成细胞（KCs）促进银屑病表型。此外，LPA还能够上调p-PKD1、p-Stat1,促进NF-κB核转位，激活PKD1相关信号通路。转录组测序发现LPA能促进CIITA、MHC-Ⅱ等分子的表达，CIITA基因启动子存在Stat1结合位点。因此我们认为LPA能够作用LPAR5/PKD1信号轴，通过Stat1/CIITA上调MHC-Ⅱ类分子的表达，激活KCs的抗原递呈功能；通过NF-κB激活KCs的分泌功能，促进银屑病炎症因子的表达与分泌，最终促进银屑病。本项目通过EMSA、CHIP、KCs与T细胞共培养等方法研究LPA活化KCs的具体作用机制，为银屑病的研究提供新的思路和策略

LPA(lysophosphatidic acids) and its receptors have a wide range of biological functions, but their role has not been elucidated in psoriasis. Our previous results showed that LPA receptor5 (LPAR5) was highly expressed in psoriatic lesions, and LPA abundance was significantly increased in the plasma, skin lesions of psoriatic mice and psoriasis patient's plasma, which facilitates the phenotype of psoriasis through keratinocytes (KCs). Furthermore, LPA up-regulates p-PKD1 and p-Stat1 and promotes NF-κB nuclear translocation, which activates PKD1 signaling pathway. The results of RNA Seq showed that LPA could promote the expression of CIITA, MHC-Ⅱ, meanwhile, there were Stat1 recognized motif in the promoter of CIITA gene. Therefore, we proposed that LPA promotes psoriatic pathogenesis through LPAR5/PKD1 axis, which raises the expression of MHC-II through Stat1/CIITA activating the antigen presentation function of KCs, while, activates the function of KCs through NF-κB to benefit the expression and secretion of psoriasis-related factors. In this study, EMSA, CHIP, KCs and T cell co-culture will be performed to study the role of LPA in psoriasis through activation KCs, providing novel clues and strategies for psoriasis.