皮肤间充质干细胞通过其分泌的sTNFR1抑制Th17细胞的分化

T helper 17 (Th17) cells play an important role in multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE). However, much remains unclear about the regulatory factorscontrolling the differentiation of Th17 cells. Mesenchymal stem cells (MSCs) have emerged as a promising candidate for inhibiting Th17 cell differentiation and autoimmune diseases. Despite several molecules have been linked to the immunomodulatory function of MSCs, many of other key MSC-secreted regulators that are involved in inhibiting Th17 cell polarizationare ill defined. In our previous study, we demonstrated that the intraperitoneal administration of skin-derived MSCs (S-MSCs) suppressed the development of EAE in mice. Moreover, under an inflammatory condition we demonstrated that S-MSCs produced high amount of soluble TNF receptor 1 (sTNFR1) which binds TNF-α, In this project, we focused on the function of sTNFR1 on the differentiation of Th17 cells and the role of TNF-α on the modulation of Th17 cells and APCs. Thus, our data will uncover a previously unrecognized mechanism for MSCs therapy in autoimmune diseases.

Th17细胞在MS（multiple sclerosis）和EAE（experimental autoimmune encephalomyelitis）疾病发生发展过程中扮演重要角色。目前关于调控Th17细胞诱导分化的相关因子还知之甚少。MSCs能够抑制Th17细胞的分化和治疗自身免疫性疾病。尽管已经鉴定出一些MSCs分泌的免疫调节分子，但MSCs分泌的其他一些抑制Th17细胞分化的细胞因子还不清楚。我们前期的研究结果显示注射SMSCs可以治疗EAE，SMSCs能够抑制Th17细胞的分化，SMSCs活化后能产生高水平的sTNFR1，本项目主要调查sTNFR1对Th17细胞分化的影响以及与sTNFR1特异性结合的TNF-α对Th17细胞和抗原提呈细胞（APCs）的调控作用，最终揭示SMSCs治疗自身免疫性疾病的新机制。

Th17细胞在自身免疫性疾病发生发展过程中发挥重要作用。目前已知TGF-β和IL-6是Th17细胞分化的关键因子。但其他因子对Th17细胞分化的调控还知之甚少。MSCs能够抑制Th17细胞的分化和治疗自身免疫性疾病。那么是否MSC分泌的细胞因子参与了抑制Th17细胞分化呢？我们的研究结果显示SMSCs能够缓解EAE临床症状，并且SMSCs能够抑制Th17细胞的分化，利用蛋白质芯片技术筛选出SMSCs活化后分泌大量的sTNFR1，sTNFR1可中和TNF-α的生物学活性。TNF-α可以促进Th17细胞的分化。干扰TNFR1后发现S-MSCs治疗EAE能力明显减弱。终上S-MSCs通过其分泌的sTNFR1来中和TNF-α从而抑制TNF-α对Th17细胞分化的促进作用，最终达到治疗EAE疾病的目的。我们的研究为更全面的了解 MSCs 在治疗自身免疫性疾病过程中的作用提供了新观点，也为 MSCs 用于临床转化提供了实验依据。