miR-210在银屑病Th17细胞分化异常中的作用及机制研究

The increased Th17 cells in the peripheral blood and skin lesion of psoriasis induce and aggravate the skin damage of psoriasis through secrecting a lot of inflammatory cytokines. Presently, the mechanism of regulating Th17 cell differentiaton in the peripheral blood and skin lesion of psoriasis is still unclear. MicroRNAs play important roles in many processes of pathogenesis through regulating gene expression. Our previous studies showed that expression of miR-210 was up-regulated significantly in peripheral CD4+ T cells and lesional skin from psoriasis patients. Overexpression of exogenous miR-210 increased IFN-γ secretion of CD4+ T cells in vitro. Bio-information analysis showed that STAT6, a key negative regulator of Th1 and Th17 differentiation, may be a potential target of miR-210. Our project will identify the role of miR-210 in regulating Th17 cell differentiation and skin lesion of psoriasis in vitro and in vivo. Furthermore, we will investigate the cause of miR-210 up-regulation in CD4+ T cells of peripheral blood and lesional skin from psoriasis patients (epigenetic regulation) and the mechanism of Th17 cell differentiation induced by increased miR-210 expression (regulation of downstream gene STAT6). This project will be helpful in revealing the pathogenesis of psoriasis and will provide a novel target for psoriasis treatment.

银屑病外周血和皮损组织中Th17细胞异常增加，通过分泌大量炎症因子诱发和加重银屑病皮损。目前导致银屑病外周血和皮损组织中Th17细胞分化异常的机制尚不清楚。microRNAs在多种生理和病理过程中发挥重要作用。我们的前期研究发现miR-210在银屑病外周血CD4+T细胞和皮损组织中表达均显著升高，过度表达miR-210可显著促进CD4+T细胞分泌IFN-γ。生物信息学预测显示负调控Th1和Th17分化的重要基因STAT6是miR-210的潜在靶基因。本项目拟通过细胞与在体动物实验，查明miR-210在调控Th17细胞分化及银屑病皮损发生发展中的重要作用。在此基础上，探讨银屑病皮损组织和外周血CD4+T细胞miR-210表达升高的原因（表观遗传调控）以及miR-210表达升高促Th17细胞分化的机制（调控下游靶基因STAT6）。该研究将有助于揭示银屑病的发病机制，并为银屑病的治疗提供新靶点。

寻常型银屑病（Psoriasis Vulgaris，PV）是一种T细胞介导的慢性炎症性自身免疫性皮肤病。最近，IL-23/Th17/IL-17轴在银屑病发病机制中的作用日益凸显。然而，银屑病中Th17细胞分化异常的具体分子机制仍未阐明。我们前期研究发现microRNA-210（miR-210）在寻常型银屑病患者皮损和外周血CD4+T细胞以及银屑病小鼠模型皮损和脾脏CD4+T细胞中均表达升高，可能与银屑病患者免疫失衡相关。本项目在此基础上，深入探讨了miR-210在银屑病患者Th17细胞异常分化中的作用及机制，并进一步探索miR-210表达升高的上游机制以及其在银屑病治疗中的应用前景。研究结果显示：miR-210可以诱导Th17和Th1分化及相关细胞因子的分泌，同时可抑制Th2分化及细胞因子分泌，促进银屑病的免疫失衡。miR-210基因敲除可以显著改善咪喹莫特诱导（IMQ）的银屑病小鼠脾脏细胞中的免疫失衡，抑制银屑病发病；而皮内注射miR-210模拟物（agomir-210）则可显著促进并加重IMQ诱导的银屑病小鼠发病。我们利用生物信息学预测发现，STAT6可能为miR-210下游潜在靶基因，进一步通过luciferase、RIP及功能实验证实STAT6确实为miR-210的靶基因，介导miR-210对Th细胞分化的作用。此外，我们还发现，TGF-β可以诱导HIF-1α表达升高，进而招募P300促进miR-210启动子区组蛋白H3乙酰化（H3ac），上调miR-210的表达。通过以上体内体外实验，我们首次证明TGF-β通过表观遗传学机制调控银屑病中miR-210的表达上调，且miR-210通过下游靶基因STAT6进一步调控Th细胞分化，参与银屑病的发生发展。该研究进一步完善了银屑病的发病机制，为银屑病治疗提供新的干预靶点。