Affiliated Eye Hospital of Nanchang University, Nanchang University School of Ophthalmology & Optometry, Jiangxi Provincial Key Laboratory for Ophthalmology, Jiangxi Research Institute of Ophthalmology & Visual Science, Nanchang 330006, PR China.
Affiliated Eye Hospital of Nanchang University, Nanchang University School of Ophthalmology & Optometry, Jiangxi Provincial Key Laboratory for Ophthalmology, Jiangxi Research Institute of Ophthalmology & Visual Science, Nanchang 330006, PR China.
Int Immunopharmacol. 2023 Jun;119:110171. doi: 10.1016/j.intimp.2023.110171. Epub 2023 Apr 14.
Pyroptosis, an inflammasome-mediated mode of death, plays an important role in glaucoma. It has been shown that regulating the mTOR pathway can inhibit pyroptosis. Unfortunately, whether rapamycin (RAPA), a specific inhibitor of the mTOR pathway, can inhibit optic nerve crush (ONC)-induced pyroptosis to protect retinal ganglion cells (RGCs) has not been investigated. Our research aimed to confirm the effect of intravitreal injection of RAPA on RGCs. Furthermore, we used the ONC model to explore the underlying mechanisms. First, we observed that intravitreal injection of RAPA alleviated RGC damage induced by various types of injury. We then used the ONC model to further explore the potential mechanism of RAPA. Mechanistically, RAPA not only reduced the activation of glial cells in the retina but also inhibited retinal pyroptosis-induced expression of inflammatory factors such as nucleotide-binding oligomeric domain-like receptor 3 (NLRP3), apoptosis-associated speckle-like protein containing a CARD (ASC), N-terminal of gasdermin-D (GSDMD-N), IL-18 and IL-1β. Moreover, RAPA exerted protective effects on RGC axons, possibly by inhibiting glial activation and regulating the mTOR/ROCK pathway. Therefore, this study demonstrates a novel mechanism by which RAPA protects against glaucoma and provides further evidence for its application in preclinical studies.
细胞焦亡是一种炎症小体介导体细胞死亡的方式，在青光眼的发生发展中发挥着重要作用。研究表明，调控 mTOR 通路可以抑制细胞焦亡。然而，mTOR 通路的特异性抑制剂雷帕霉素（rapamycin，RAPA）是否可以抑制视神经挤压（optic nerve crush，ONC）诱导的细胞焦亡从而保护视网膜神经节细胞（retinal ganglion cells，RGCs）尚未被研究。本研究旨在证实玻璃体内注射 RAPA 对 RGCs 的影响。此外，我们使用 ONC 模型进一步探讨了潜在的机制。首先，我们观察到玻璃体内注射 RAPA 可减轻各种损伤诱导的 RGC 损伤。然后，我们使用 ONC 模型进一步探讨 RAPA 的潜在机制。机制上，RAPA 不仅减少了视网膜中胶质细胞的激活，还抑制了视网膜细胞焦亡诱导的炎症因子如核苷酸结合寡聚结构域样受体 3（nucleotide-binding oligomeric domain-like receptor 3，NLRP3）、凋亡相关斑点样蛋白包含一个 CARD（apoptosis-associated speck-like protein containing a CARD，ASC）、gasdermin-D（GSDMD-N）、IL-18 和 IL-1β 的表达。此外，RAPA 对 RGC 轴突发挥了保护作用，可能通过抑制胶质细胞激活和调节 mTOR/ROCK 通路。因此，本研究揭示了 RAPA 防治青光眼的新机制，为其在临床前研究中的应用提供了进一步的证据。
