Huang Jingqiu, Chang Zhaohui, Liu Lian, Lai Cheng, Deng Xizhi, Jiang Bin, Ke Min
Department of Ophthalmology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China.
Invest Ophthalmol Vis Sci. 2025 Jun 2;66(6):77. doi: 10.1167/iovs.66.6.77.
Optic nerve crush (ONC) is an animal model that induces optic nerve injury and retinal ganglion cell (RGC) death, which is partly mediated by activated microglia secreting cytokines. This study explores the role of the CCL5/CCR5 pathway in RGC damage and evaluates maraviroc, a CCR5 inhibitor, as a potential therapeutic agent.
Bioinformatic analysis of glaucoma datasets (GSE142881 and GSE26299) identified Ccr5 as a key gene linked to acute or chronic RGC injury. The ONC model was used to evaluate the neuroprotective effects of maraviroc or sh-Ccr5 using immunofluorescence, TUNEL staining, optical coherence tomography (OCT), and electrophysiological tests. Co-culture of neuro2a cells with activated BV2 cells examined mechanisms, and intravitreal maraviroc safety and efficacy were evaluated using histological and molecular assays.
CCR5 was significantly associated with RGC injury in both datasets. Inhibition of CCR5 via maraviroc preserved RGC structure, maintained ganglion cell complex (GCC) thickness, and improved retinal function in the ONC model. Mechanistically, CCR5 inhibition prevented Cathepsin S (CTSS) downregulation and neuron apoptosis induced by ONC or activated microglia. Intravitreal maraviroc administration was safe, preserving retinal structure and RGC count in non-injured eyes while reducing RGC damage in ONC-injured eyes.
Microglial activation in glaucoma upregulates CCL5, triggering CCR5-mediated RGC apoptosis via CTSS downregulation. Maraviroc effectively reduces RGC death and optic nerve damage, offering a promising neuroprotective strategy for treatment of optic nerve injury.
视神经挤压伤（ONC）是一种可诱导视神经损伤和视网膜神经节细胞（RGC）死亡的动物模型，部分是由活化的小胶质细胞分泌细胞因子介导的。本研究探讨CCL5/CCR5通路在RGC损伤中的作用，并评估CCR5抑制剂马拉维若作为一种潜在治疗药物的效果。
对青光眼数据集（GSE142881和GSE26299）进行生物信息学分析，确定Ccr5是与急性或慢性RGC损伤相关的关键基因。使用ONC模型，通过免疫荧光、TUNEL染色、光学相干断层扫描（OCT）和电生理测试来评估马拉维若或sh-Ccr5的神经保护作用。将neuro2a细胞与活化的BV2细胞共培养以研究机制，并使用组织学和分子分析评估玻璃体内注射马拉维若的安全性和有效性。
在两个数据集中，CCR5均与RGC损伤显著相关。在ONC模型中，通过马拉维若抑制CCR5可保留RGC结构，维持神经节细胞复合体（GCC）厚度，并改善视网膜功能。从机制上讲，抑制CCR5可防止组织蛋白酶S（CTSS）下调以及ONC或活化小胶质细胞诱导的神经元凋亡。玻璃体内注射马拉维若是安全的，在未受伤的眼睛中可保留视网膜结构和RGC数量，同时减少ONC损伤眼睛中的RGC损伤。
青光眼中的小胶质细胞活化会上调CCL5，通过CTSS下调触发CCR5介导的RGC凋亡。马拉维若可有效减少RGC死亡和视神经损伤，为治疗视神经损伤提供了一种有前景的神经保护策略。
