背景:Th17细胞的异常分化已被确定为类风湿关节炎(RA)发展的关键因素。BLIMP1在调节浆细胞分化中起关键作用,T辅助细胞分化和Treg细胞分化。外泌体注射或骨髓间充质干细胞(BMSC)移植治疗可减少RA的关节损伤。但确切的监管机制仍不清楚。
方法:我们将BMSC来源的外泌体注射到RA小鼠体内,然后对小鼠踝关节进行组织学分析。我们体外培养CD4+T细胞,然后加入有或没有si-TUG1的外泌体,并诱导Th17细胞和Treg细胞的分化,然后用流式细胞仪检测Th17细胞和Treg细胞的比例。此外,我们将外泌体注射到sh-NC或sh-BLIMP1治疗的RA小鼠中,然后对踝关节进行组织学分析。
结果:我们的研究结果表明,外泌体处理降低了分化的Th17细胞的比例,同时增加Treg细胞的比例。我们观察到Exosi-TUG1组Th17细胞比例增加,Treg细胞比例降低。我们在Exo组中观察到小鼠外周血和体外培养的CD4T细胞中BLIMP1表达的增加。相反,Exosi-TUG1组显示BLIMP1表达减少。值得注意的是,抑制BLIMP1表达导致外泌体治疗效果的逆转。
结论:我们的发现表明,BMSC来源的外泌体通过携带LncTUG1的外泌体促进BLIMP1的表达,可以调节Th17细胞和Treg细胞之间的平衡。这种机制最终减轻了RA造成的损害,提示富含LncTUG1的BMSC来源的外泌体有望成为治疗RA的潜在治疗方法。
BACKGROUND: Aberrant differentiation of Th17 cells has been identified as a critical factor in the development of rheumatoid arthritis (RA).
BLIMP1 plays a key role in regulating plasma cell differentiation, T helper cell differentiation and Treg cell differentiation. Treatment with exosome injection or bone marrow mesenchymal stem cell (BMSC) transplantation reduce joint damage in RA. But the precise regulatory mechanisms remain unclear.
METHODS: We injected BMSC-derived exosomes into RA mice, and then performed histological analysis on mouse ankle joints. We cultured CD4+ T cells in vitro, then added exosomes with or without si-TUG1 and induced the differentiation of Th17 cells and Treg cells, and then we used flow cytometry to detect the ratio of Th17 cells and Treg cells. Furthermore, we injected exosomes into sh-NC or sh-
BLIMP1-treated RA mice, and then performed histological analysis on the ankle joints.
RESULTS: The results of our study demonstrate that exosome treatment decreased the proportion of differentiated Th17 cells, while increasing the proportion of Treg cells. And we observed that the Exo si-TUG1 group had an increased proportion of Th17 cells and a decreased proportion of Treg cells. We observed an increase in
BLIMP1 expression in both the peripheral blood of mice and in CD4+ T cells cultured in vitro in the Exo group. Conversely, the Exo si-TUG1 group showed a decrease in
BLIMP1 expression. Notably, inhibiting
BLIMP1 expression led to the reversal of the therapeutic effects of exosomes.
CONCLUSIONS: Our findings suggest that BMSC-derived exosomes promote the expression of BLIMP1 through Lnc TUG1-carrying exosomes, which may modulate the balance between Th17 cells and Treg cells. This mechanism ultimately alleviates damage caused by RA, suggesting that BMSC-derived exosomes enriched in Lnc TUG1 hold promise as a potential therapeutic approach for treating RA.