外泌体lncRNA XIST通过竞争性结合miR-98靶向mTOR信号通路调控T细胞自噬在SLE发病中的作用机制研究

Abnormal T cell activation plays an important role in systemic lupus erythematosus (SLE), which is an autoimmune disease with unknown pathogenesis. Exosomes are extracellular vesicles secreted by cells, which contain multiple bioactive substances such as protein, mRNAs, miRNAs and lncRNAs. LncRNAs can exert their biological effects through interacting with miRNAs, functioning as competing endogenous RNAs, hence leading to derepression of its target mRNA. Nowadays, autophagy has attracted much new attention, however, the precise role it plays in SLE is still unclear. mTOR signaling pathway plays a critical role in autophagy regulation, however, the precise role of mTORC2 in SLE remains unclear. In our previous study, we found that lncRNA XIST is significantly overexpressed in both plasma exosomes and CD4+T cells from SLE patients, miR-98 and autophagy is downregulated in SLE patients compared with healthy donors, while Rictor (a core component of mTORC2) is upregulated, moreover, we verified that miR-98 is a gene target of lncRNA XIST, and Rictor is a gene target for miR-98. In this study, we intended to explore the role exosome-derived lncRNA XIST plays in the regulation of CD4+ T cell autophagy in the pathogenesis of SLE, thus helping to find novel therapeutic targets for SLE treatment.

SLE是以T细胞异常导致自身免疫耐受丧失为特点的自身免疫病，迄今病因未明。外泌体作为细胞分泌至胞外的囊泡性小体，其携带的lncRNA可以吸附miRNA从而参与miRNA对靶基因mRNA的表达调控。自噬作为近年来的研究热点，在SLE中的作用存在争议。mTOR信号通路是自噬通路的关键调控环节，但mTORC2（Rictor是其重要组分）在SLE中的作用尚不明确。我们预实验发现SLE血浆外泌体和CD4+T细胞中lncRNA XIST表达较正常人明显上调，CD4+T细胞miR-98表达下调、Rictor表达上调、自噬下调，并证实miR-98是lncRNA XIST的靶基因，Rictor是miR-98的靶基因。在此基础上本课题拟以SLE患者T细胞异常为切入点，探讨外泌体lncRNA XIST穿梭竞争性结合miR-98靶向mTOR信号通路对T细胞自噬的调控及其在SLE发病中的作用机制，为治疗提供新靶点。

系统性红斑狼疮一种是以T细胞异常导致自身免疫耐受丧失为特点的自身免疫性疾病，目前发病机制不明。外泌体作为细胞分泌至胞外的囊泡性小体，其携带的lncRNA通过作用于受体细胞吸附miRNA从而参与miRNA对靶基因mRNA的表达调控，以此调控受体细胞的生物学行为。自噬作为近年来的研究热点，在SLE中的作用存在争议。mTOR信号通路是自噬通路的关键调控环节，但mTORC2（Rictor是其重要组分）在SLE中的作用尚不明确。我们的研究显示SLE患者血浆外泌体和外周血CD4+T细胞中lncRNA XIST表达较健康对照者均明显升高，CD4+T细胞中Rictor/mTOR信号通路相关蛋白表达升高。miR-98是lncRNA XIST的靶基因，Rictor是miR-98的靶基因。lncRNA XIST通过竞争性结合miR-98靶向作用于Rictor从而调控Rictor/mTOR信号通路，进而调节细胞自噬和活化。SLE患者血浆外泌体中高表达的lncRNA XIST可以穿梭入CD4+T细胞中，靶向作用于miR-98从而激活Rictor/mTOR信号通路，进而抑制细胞自噬以及诱导细胞活化，从而参与SLE发病。综上，本课题以SLE患者T细胞异常为切入点，探讨了外泌体lncRNA XIST穿梭竞争性结合miR-98靶向mTOR信号通路对T细胞自噬的调控及其在SLE发病中的作用机制，这对于进一步明确SLE的发病机制，探索新的治疗靶点具有重要的科学意义和临床应用前景。