miR-214通过调节树突细胞功能调控实验性自身免疫性脑脊髓炎的作用机制研究

Experimental autoimmune encephalomyelitis (EAE) is an autoimmune inflammatory disease, mediated by T helper cells (Th) that infiltrate the central nervous system. Dendritic cells (DC) influence the differentiation of different T helper cells. Recent studies suggest that DC play a key role in the immune pathology in EAE. The inducing immune tolerance by DC plays an important role in the therapy of autoimmune diseases. However, the mechanism of DC induced tolerance is still in the exploratory stage. Our experiments found that microRNA-214 (miR-214) targeted of β-catenin protein in DC, and β-catenin is a key molecule in DC immune tolerance formation. Further experiments found that silencing miR-214 inhibited DC maturation and proinflammatory cytokine secretion, significantly alleviated EAE onset. Therefore, we hypothesized that regulation of miR-214 expression in EAE may be by affecting β-catenin, thereby indirectly or directly inhibit T cell activation and Th differentiation, inhibition of CNS inflammation, and remission EAE disease. This proposal will focus on impact of miR-214 in process of EAE occurs by influence DC and various T cell subsets differentiation balance; to study whether miR-214 influence the DC to secret inflammation factors to regulate TH17 cell differentiation directly or indirectly. The success of this study will provide promoting cellular and molecular mechanisms of EAE occurs, thereby provide a new way for MS and miR-214 associated autoimmune diseases immunotherapy.

实验性自身免疫脑脊髓炎(EAE)是由辅助性T细胞(Th)介导的中枢神经系统自身免疫炎症疾病。研究发现诱导免疫耐受DC对自身免疫性疾病的治疗起重要作用。但是，DC诱导的耐受机制尚处于探讨阶段。我们研究发现microRNA-214靶向调节DC的β-catenin蛋白，而β-catenin是DC免疫耐受形成关键信号分子。进一步实验发现沉默miR-214抑制DC细胞成熟和促炎细胞因子分泌，显著缓解EAE发病。因此，我们推测miR-214对EAE的调节作用可能通过影响β-catenin，从而间接或直接抑制T细胞激活和Th分化，缓解EAE病情。因此，本项目拟深入研究miR-214对EAE发生过程中DC和各种T细胞亚群分化平衡的影响；研究miR-214是否通过DC及其分泌的因子间接或直接调节TH17细胞分化，进而促进EAE发生的细胞和分子机制，从而为多发性硬化症治疗奠定基础。

实验性自身免疫脑脊髓炎（EAE）是人类多发性硬化症（MS）对应的成熟的动物模型。EAE是由辅助性T细胞（Th）介导的中枢神经系统自身免疫炎症疾病。研究发现诱导免疫耐受的树突细胞（DC）以及抑制Th17细胞对自身免疫性疾病的治疗起重要作用。但是，DC诱导的耐受机制尚处于探讨阶段。我们研究发现microRNA-214（miRNA-214）靶向调节DC的β-catenin蛋白，而β-catenin是DC免疫耐受形成关键信号分子。同时我们发现miR-214可靶向SMAD4进而抑制Th17细胞的分化成熟。进一步的实验发现沉默miR-214抑制DC细胞成熟和促炎细胞因子分泌，显著缓解EAE发病。因此，我们推测miR-214对EAE的调节作用可能通过影响β-catenin，从而间接或直接抑制T细胞激活和Th分化。因此，本项目拟深入研究miR-214对EAE发生过程中DC和各种T细胞亚群分化平衡的影响；研究miR-214是否通过DC及其分泌的因子间接或直接调节Th17细胞分化，进而促进EAE发生的细胞和分子机制，从而为多发性硬化症治疗奠定基础，并且可能为MS的临床诊断提供分子靶标。