ERAP1通过调控巨噬细胞影响角质形成细胞增殖、凋亡在寻常型银屑病中的作用机制研究

Inflammation and epidermal hyperplasia is the most important pathological basis of psoriasis，innate immune disorders play an important role in the pathogenesis of psoriasis.The macrophage（Mφ），as a key immune cells, can secret of inflammatory cytokines while stimulated by external factors and induce innate immune disorder. Both GWAS and Exon sequencing confirmed ERAP1 associated with psoriasis. Recent studies have shown that ERAP1 play an important role in innate immunity by enhancing Mφ and NK cell activity and stimulating the secretion of inflammatory factors. We observed ERAP1 expression difference in different stage of psoriasis in our previous study. So we proposed "ERAP1 was involved in pathogenesis of psoriasis by inducing Mφ secret inflammatory cytokines and inhibiting apoptosis pathway of KC" . We observed the effect of functional SNP-associated variants of ERAP1 on Mφ secretory function in vitro; evaluate the effects of actived macrophages on cell biology of HaCaT cells by cell co-culture experiment; observe effect of ERAP1 on the proliferation, apoptosis and the secretion function of KC by in vitro experiments and population studies and the possible mechanism. The study open a window for the study of pathogenesis of psoriasis, and provide the theoretical basis for seeking the new therapeutic targets.

炎症和表皮增生是银屑病最主要的病理基础，天然免疫紊乱在银屑病发病中起重要作用。Mφ细胞作为一种关键的免疫细胞，在外界因素的刺激下分泌炎性细胞因子，诱导天然免疫紊乱。GWAS研究及外显子测序均提出ERAP1基因与银屑病发病相关，近期研究表明ERAP1可增强Mφ活性，刺激炎性因子分泌，在天然免疫中发挥重要作用。本项目在我们前期工作观察到ERAP1在银屑病不同病期表达差异的基础上，提出“ERAP1 通过促Mφ细胞分泌炎性细胞因子及影响KC细胞凋亡双重途径参与银屑病发病”的假设，通过体外实验观察ERAP1功能性SNP突变体对人Mφ分泌功能影响；通过细胞共培养试验，观察激活的Mφ细胞对HaCaT细胞生物学的影响; 通过体外实验及人群研究观察ERAP1对KC细胞增殖、凋亡及分泌功能的影响及可能作用机制，为银屑病发病机制的研究提供新的视角，对寻找新的治疗靶点提供理论依据。