State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Eye Institute of Shandong First Medical University, Qingdao, 266071, China.
Eye Hospital of Shandong First Medical University (Shandong Eye Hospital), Jinan, 250117, China.
Adv Sci (Weinh). 2023 Dec;10(34):e2304922. doi: 10.1002/advs.202304922. Epub 2023 Oct 23.
Immune rejection and side effects of long-term administration of immunosuppressants are the two major obstacles to allograft acceptance and tolerance. The immunosuppressive extracellular vesicles (EVs)-based approach has been proven to be effective in treating autoimmune/inflammatory disorders. Herein, the anti-rejection advantage of exosomes (Rapa-Exo) from rapamycin-conditioned myeloid-derived suppressor cells (MDSCs) over exosomes (Exo-Nor) from the untreated MDSCs is shown. The exosomal small RNA sequencing and loss-of-function assays reveal that the anti-rejection effect of Rapa-Exo functionally relies on miR-181d-5p. Through target prediction and double-luciferase reporter assay, Kruppel-like factor (KLF) 6 is identified as a direct target of miR-181d-5p. Finally, KLF6 knockdown markedly resolves inflammation and prolongs the survival of corneal allografts. Taken together, these findings support that Rapa-Exo executes an anti-rejection effect, highlighting the immunosuppressive EVs-based treatment as a promising approach in organ transplantation.
免疫排斥和长期使用免疫抑制剂的副作用是同种异体移植接受和耐受的两大障碍。基于免疫抑制细胞外囊泡（EVs）的方法已被证明可有效治疗自身免疫/炎症性疾病。本文展示了雷帕霉素预处理髓源抑制性细胞（MDSC）来源的外泌体（Rapa-Exo）比未经处理的 MDSC 来源的外泌体（Exo-Nor）在抗排斥方面的优势。外泌体小 RNA 测序和功能丧失实验表明，Rapa-Exo 的抗排斥作用功能上依赖于 miR-181d-5p。通过靶基因预测和双荧光素酶报告基因实验，鉴定出 Kruppel 样因子 6（KLF6）是 miR-181d-5p 的直接靶基因。最后，敲低 KLF6 可显著缓解炎症并延长角膜同种异体移植物的存活时间。综上所述，这些发现支持 Rapa-Exo 发挥抗排斥作用，突出了基于免疫抑制性 EVs 的治疗方法在器官移植中的应用前景。
