Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China; Key Laboratory of Orthopaedics of Zhejiang Province, Wenzhou, Zhejiang, China; The Second Clinical Medical College of Wenzhou Medical University, Wenzhou, China.
The Second Affiliated College of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China.
Int Immunopharmacol. 2024 Dec 5;142(Pt A):113072. doi: 10.1016/j.intimp.2024.113072. Epub 2024 Sep 6.
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.
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.
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.
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.
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、辅助性 T 细胞分化和 Treg 细胞分化方面发挥着关键作用。外泌体注射或骨髓间充质干细胞（BMSC）移植治疗可减少 RA 中的关节损伤。但确切的调节机制尚不清楚。
我们将 BMSC 来源的外泌体注入 RA 小鼠体内，然后对小鼠踝关节进行组织学分析。我们在体外培养 CD4 T 细胞，然后加入含有或不含有 si-TUG1 的外泌体，并诱导 Th17 细胞和 Treg 细胞分化，然后用流式细胞术检测 Th17 细胞和 Treg 细胞的比例。此外，我们将外泌体注入 sh-NC 或 sh-BLIMP1 处理的 RA 小鼠体内，然后对踝关节进行组织学分析。
我们的研究结果表明，外泌体治疗降低了分化的 Th17 细胞的比例，同时增加了 Treg 细胞的比例。我们观察到 Exo si-TUG1 组 Th17 细胞的比例增加，Treg 细胞的比例减少。我们观察到 Exo 组小鼠外周血和体外培养的 CD4 T 细胞中 BLIMP1 表达增加。相反，Exo si-TUG1 组 BLIMP1 表达减少。值得注意的是，抑制 BLIMP1 表达导致外泌体的治疗效果逆转。
我们的研究结果表明，BMSC 来源的外泌体通过携带 Lnc TUG1 的外泌体促进 BLIMP1 的表达，可能调节 Th17 细胞和 Treg 细胞之间的平衡。这种机制最终缓解了 RA 引起的损伤，表明富含 Lnc TUG1 的 BMSC 衍生外泌体有望成为治疗 RA 的一种潜在治疗方法。
