IL-17-JMJD3信号轴对间充质干细胞治疗EAE的调控作用及机制研究

项目名称： IL-17-JMJD3信号轴对间充质干细胞治疗EAE的调控作用及机制研究

项目编号： No.81471217

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 万兵

作者单位： 上海交通大学

项目金额： 70万元

中文摘要： 自身反应Th17细胞异常活化所致中枢神经系统脱髓鞘损伤是多发性硬化（MS）及其模型EAE的关键致病机制。间充质干细胞（MSC）因其抗炎和组织修复潜能成为治疗MS的研究热点，但Th17细胞是否调控MSC免疫调节和促髓鞘修复功能未知。项目组发现，Th17产生的IL-17A、IL-17F协同诱导骨髓MSC抑制淋巴细胞增殖及调控小胶质细胞系BV2表达M1/M2型细胞因子的功能；IL-17促进MSC表达组蛋白H3K27去甲基化酶JMJD3；JMJD3抑制剂GSK-J4预处理MSC明显降低其EAE疗效。藉此，本申请项目拟研究IL-17-JMJD3信号轴调控MSC免疫调节（影响T细胞活化、增殖、Th17/Treg细胞平衡）和髓鞘修复功能（促进小胶质细胞M1/M2类型转换，驱动少突胶质前体细胞分化成熟为少突胶质细胞）治疗EAE的表观遗传调控机制，为探索靶向调控JMJD3增强MSC对MS疗效奠定基础。

中文关键词： IL-17-JMJD3信号轴；实验性自身免疫性脑脊髓炎；间充质干细胞；免疫调节；髓鞘修复

英文摘要： Multiple Sclerosis（MS）is a demyelinating disease of the central nervous system (CNS) with a very high rate of disability. Current therapies can only ameliorate the symptoms but none of them is a cure. T helper 17 cells (Th17) play a critical role in the pathogenesis of MS and experimental autoimmune encephalomyelitis (EAE), which is a common used animal model for MS. Mesenchymal stem cells (MSCs) display immunomodulatory property and tissure repair capability, thus represent a promosing therapy for MS. The crosstalk between the inflammaoty microenvironment and MSCs determines the therapeutic outcome of MSCs. However, whether Th17 cells in the inflammaoty microenvironment of MS/EAE regulate the immunomodulatory property and remyelination accelerating capability of MSCs and the underlying cellular and molecular mechanisms remain elusive. We found that the representative cytokines of T helper (Th)17 cells, IL-17A and IL-17F, synergistically induced MSCs to suppress immune cell proliferation and regulate M1/M2 type cytokine production by microglia,as well as upregulated the expression of JMJD3, which is a histone H3K27 demethylase. Pretreatment of MSCs with GSK-J4, a selective inhibitor of JMJD3, decresased the therapeutic efficacy of MSCs in EAE. Therefore, we plan to work on the hypothesis that IL-17-JMJD3 axis regulates the immunomodulatory function of MSCs on the activation and proliferation of T cells, differentiation of Th17 cells and regulatory T cells (Tregs), as well as the switch of M1 type microglia to M2 type microglia,subsequently, M2 type microglia promote the differentiaton of oligodendrocyte progenitor cells (OPC) into oligodendrocytes (OLG) and remyelination process. This project will be helpful to gain insights into the cellular and molecular mechansims, and more importantly, epigenetic regulatory mechansims of therapeutic effects of MSCs on EAE as well as target JMJD3 to enhance the therapeutic effect of MSCs on MS and other autoimmune diseases.

英文关键词： IL-17-JMJD3 axis;experimental autoimmune encephalomyelitis;mesenchymal stem cell;immunoregulation;myelin repair