外泌体通过miR-3926调控T细胞自噬和凋亡在SLE发病中的作用机制研究

Systemic lupus erythematosus (SLE) is an autoimmune disease with unknown pathogenesis, and abnormal T cell activation plays a crucial role in its development. Exosomes are extracellular vesicles secreted by different types of cells, which contain multiple bioactive substances such as protein, mRNAs and miRNAs. As a novel type of intercellular messengers in cell communications, exosomes can be released into the extracellular environment and modify the function of recipient cells through transfer of miRNAs. MiRNAs are small non-coding RNAs, which controls gene expression by acting on their target mRNAs. Nowadays, the role of exosomes in immune cells regulation in the etiology of SLE have attracted much new attention. Autophagy and apoptosis are both programmed cell death processes, both of which have been demonstrated to play an important role in the maintaining of lymphocyte homeostasis, however, the precise function of them and their crosstalk in SLE remains unclear. In our previous study, we found that miR-3926 is significantly overexpressed in both plasma exosomes and CD4+T cells from SLE patients, and autophagy-related gene 5 (ATG5) and autophagy is downregulated in SLE patients compared with healthy donors, while apoptosis is upregulated, moreover, we verified that ATG5 is a gene target for miR-3926. Thus we thought that the exosome-derived miR-3926 might be the source of the overexpressed miR-3926 in SLE CD4+ T cells. In this study, we intended to explore the role exosome-derived miR-3926 plays in the crosstalk of autophagy and apoptosis in the pathogenesis of SLE, and help to find therapeutic targets for SLE treatment.

SLE是一种以T细胞异常导致自身免疫耐受丧失为特点的自身免疫病，迄今病因不明。外泌体作为细胞分泌至胞外的囊泡性小体，其携带的miRNA通过作用于受体细胞靶mRNA而调控细胞生物学行为，其在SLE中对免疫细胞的调控成为新的研究热点。自噬和凋亡作为两种程序性细胞死亡方式，在淋巴细胞稳态的维持中发挥重要作用，然而两者在SLE中的作用仍不明确。我们前期研究发现SLE血浆外泌体和CD4+T细胞中miR-3926表达较正常对照明显上调，CD4+T细胞自噬下调、凋亡上调，并证实自噬相关基因5（ATG5）是miR-3926的靶基因。由此猜想：SLE外泌体中异常升高的miR-3926或许是CD4+T细胞中异常表达的miR-3926的来源。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miR-3926穿梭靶向ATG5基因对T细胞自噬和凋亡的调控及其在SLE发病中的具体作用机制，为治疗提供新靶点。

SLE是一种以T细胞异常导致自身免疫耐受丧失为特点的严重危害人类健康的自身免疫病，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miRNA通过作用于受体细胞靶mRNA而调控细胞生物学行为，其在SLE中对免疫细胞的调控成为新的研究热点。自噬和凋亡作为两种程序性细胞死亡方式，在淋巴细胞稳态的维持中发挥重要作用，然而两者在SLE中的作用仍不明确。我们的研究显示SLE患者血浆外泌体和外周血CD4+T细胞中miR-3926表达较正常对照均明显上调，CD4+T细胞自噬下调、凋亡上调，并证实自噬相关基因5、12、16L1（ATG5、ATG12、ATG16L1）均是miR-3926的靶基因，且miR-3926可以通过靶向作用于ATG5、ATG12和ATG16L1调节细胞自噬，从而影响细胞凋亡及活化。SLE患者血浆外泌体可穿梭入健康人外周血CD4+T细胞中，其携带的异常升高的miR-3926可以改变细胞中miR-3926的水平，进而影响其自噬、凋亡及活化水平，从而参与SLE发病。SLE患者血浆外泌体可携带外源性miR-3926 inhibitor穿梭入SLE患者自体CD4+T细胞中，从而改变细胞中miR-3926的水平，进而影响其自噬、凋亡及活化水平，为SLE的治疗提供新靶点。动物实验也得到了与上述体外细胞实验一致的结果。综上，本课题以SLE患者T细胞异常为切入点，探讨了外泌体miR-3926穿梭靶向ATG5、ATG12和ATG16L1基因对T细胞自噬和凋亡的调控及其在SLE发病中的具体作用机制，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。