Department of Ophthalmology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Clinical Research Center of Ophthalmic Disease, Changsha, Hunan, China.
State Key Laboratory of Respiratory Disease, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, Guangdong 510120, China; Guangzhou National Laboratory, Guangzhou, Guangdong 510005, China.
Am J Transplant. 2023 Sep;23(9):1359-1374. doi: 10.1016/j.ajt.2023.05.017. Epub 2023 May 22.
Rapamycin is an immunosuppressive drug that is widely used in the postsurgery management of transplantation. To date, the mechanism by which rapamycin reduces posttransplant neovascularization has not been fully understood. Given the original avascularity and immune privilege of the cornea, corneal transplantation is considered as an ideal model to investigate neovascularization and its effects on allograft rejection. Previously, we found that myeloid-derived suppressor cells (MDSC) prolong corneal allograft survival through suppression of angiogenesis and lymphangiogenesis. Here, we show that depletion of MDSC abolished rapamycin-mediated suppression of neovascularization and elongation of corneal allograft survival. RNA-sequencing analysis revealed that rapamycin dramatically enhanced the expression of arginase 1 (Arg1). Furthermore, an Arg1 inhibitor also completely abolished the rapamycin-mediated beneficial effects after corneal transplantation. Taken together, these findings indicate that MDSC and elevated Arg1 activity are essential for the immunosuppressive and antiangiogenic functions of rapamycin.
雷帕霉素是一种免疫抑制剂，广泛用于移植后的术后管理。迄今为止，雷帕霉素减少移植后新生血管形成的机制尚未完全阐明。鉴于角膜最初的无血管性和免疫特权，角膜移植被认为是研究新生血管形成及其对同种异体移植物排斥反应影响的理想模型。以前，我们发现髓源抑制细胞（MDSC）通过抑制血管生成和淋巴管生成来延长角膜同种异体移植物的存活时间。在这里，我们发现耗尽 MDSC 会消除雷帕霉素介导的对新生血管形成和角膜同种异体移植物存活时间延长的抑制作用。RNA 测序分析表明，雷帕霉素显著增强了精氨酸酶 1（Arg1）的表达。此外，Arg1 抑制剂也完全消除了角膜移植后雷帕霉素介导的有益作用。综上所述，这些发现表明 MDSC 和升高的 Arg1 活性对于雷帕霉素的免疫抑制和抗血管生成功能是必需的。
