黄芪皂苷激活CD4+T细胞Egr-1-Foxp3通路促Treg介导的多发性硬化症髓鞘保护作用机制研究

多发性硬化症（MS）是自身免疫神经脱髓鞘病变，目前无治愈药物。最新研究发现Treg细胞免疫抑制同时还促进髓鞘再生，从而为治疗MS的新药研发提供了新思路。我们首次发现黄芪皂苷在MS模型EAE小鼠和CPZ诱导脱髓鞘小鼠中促使Foxp3+Treg细胞分化，促进髓鞘再生，防治疾病，其作用与激活CD4+T细胞Egr-1有关；而Egr-1可直接调控Foxp3表达，促进Treg细胞分化；Egr-1 KO鼠Treg细胞分化减少，髓鞘再生降低；由此我们提出假说：黄芪皂苷激活CD4+T细胞Egr-1，促使Treg细胞分化保护髓鞘。我们拟运用CD4+T细胞Egr-1条件敲除、ERE-EGFP转基因、Egr-1 KO小鼠及OPC-DRG细胞共培养等模型，结合生物信息、分子生物、神经免疫药理等技术方法，验证该假说，以期为靶向Egr-1，促免疫抑制和髓鞘再生双重作用MS新药开发及黄芪皂苷临床应用的物质基础提供依据。

Multiple sclerosis (MS) is an autoimmune demyelination disease. Currently, there is no intervention that can completely cure the disease. Recent study disclosed that Treg cells not only play a role in immunosuppression of other encephalomyelitic T helper cells, such as Th17, but also facilitate remyelination in central nervous system (CNS), which provides new insight into the development of MS therapeutic drugs. Our previous studies found that astragalosides, the major bioactive components of Astragalus membranaceus, attenuated the severity of experimental autoimmune encephalomyelitis (EAE) and cuprizone (CPZ)-induced mice by promoting the differentiation of Foxp3+ Treg cells and remyelination, which was closely related with the activation of the transcription factor, early growth response 1 (Egr-1), in CD4+ T cells. Simultaneously, astragalosides were shown to activate forxhead box protein 3 (Foxp3) in CD4+ T cells. When Egr-1 was knocked out, the EAE and demyelination in mice was aggravated with less Tregs and remyelination. Based on the aforementioned facts, we hypothesized that astragalosides protect myelin sheath by enhancing Treg differentiation through activation of Egr-1 in CD4+T cells. To test the hypothesis, in the present proposal, we will explore the role of CD4+ T cell Egr-1 in the protective effect of astragalosides on myelin sheath by using CD4+ T cell Egr-1 KO mice, ERE-EGFP transgenic mice, Egr-1 KO mice, OPC-DRG co-culture cell models together with bioinformatic, biomolecular and neuroimmunopharmacologic techniques. Upon the completion of the project, we hope to confirm the possibility of development of MS therapeutic drugs with double efficacy on immunosuppression and remyelination by targeting Egr-1 in CD4+ T cells. At the same time, we hope the findings could provide theoretical basis for the clinical application of astragalosides in the therapy of MS.