Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai, 200031, China.
Key Laboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai, 200031, China; Shanghai Key Laboratory of Visual Impairment and Restoration, Fudan University, Shanghai, 200031, China; NHC Key Laboratory of Myopia (Fudan University), Chinese Academy of Medical Sciences, Shanghai, 200031, China.
Exp Eye Res. 2021 Nov;212:108792. doi: 10.1016/j.exer.2021.108792. Epub 2021 Oct 14.
P2X7R is a vital modifier of various inflammatory and immune-related diseases. However, the immunomodulatory effects of P2X7R on corneal allograft rejection remains unknown. Here we showed that P2X7R expression was significantly upregulated in corneal grafts of allogeneic transplant mice. Pharmacological blockage of P2X7R remarkably prolonged graft survival time, and reduced inflammatory cell infiltration in corneal grafts, in particular Th1/Th17 cells. Meanwhile, the frequencies of Th1/Th17 cells in draining lymph nodes were significantly decreased in P2X7R blocked allogeneic mice. Further results showed that the effect of P2X7R on promoting Th1/Th17 mediated immune responses in corneal allograft rejection relied heavily on its activation on the NLRP3/caspase-1/IL-1β axis, while P2X7R blockage could mitigate such activation. Nevertheless, the addition of IL-1β in vivo abrogated the protective effect of P2X7R blockage on promoting corneal graft survival. These findings demonstrate that blockage of P2X7R can substantially alleviate corneal allograft rejection and promote grafts survival, highlighting it as a promising target for preventing or treating corneal allograft rejection.
P2X7R 是多种炎症和免疫相关疾病的重要调节剂。然而，P2X7R 对角膜同种异体移植物排斥的免疫调节作用尚不清楚。在这里，我们发现 P2X7R 在同种异体移植小鼠的角膜移植物中表达显著上调。P2X7R 的药理学阻断显著延长了移植物的存活时间，并减少了角膜移植物中的炎症细胞浸润，特别是 Th1/Th17 细胞。同时，在 P2X7R 阻断的同种异体小鼠中，引流淋巴结中 Th1/Th17 细胞的频率也显著降低。进一步的结果表明，P2X7R 促进 Th1/Th17 介导的角膜同种异体移植排斥反应的作用在很大程度上依赖于其在 NLRP3/caspase-1/IL-1β 轴上的激活，而 P2X7R 的阻断可以减轻这种激活。然而，体内添加 IL-1β 会消除 P2X7R 阻断对促进角膜移植物存活的保护作用。这些发现表明，阻断 P2X7R 可以显著减轻角膜同种异体移植物排斥反应并促进移植物存活，这突显了它作为预防或治疗角膜同种异体移植物排斥反应的有前途的靶点。
