Investigative ophthalmology & visual science · 2025
Maraviroc Prevents Optic Nerve Injury-Induced Retinal Ganglion Cell Apoptosis by Modulating the CCL5/CCR5/CTSS Axis.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Huang Jingqiu, Chang Zhaohui, Liu Lian, Lai Cheng, Deng Xizhi, Jiang Bin, Ke Min
Аннотация
PURPOSE: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.