Targeting cGAS-STING signaling protects retinal ganglion cells from DNA damage-induced cell loss and promotes visual recovery in glaucoma

Background: Glaucoma is an optic neurodegenerative disease. Retinal ganglion cells (RGCs) are the fundamental neurons in the trabecular meshwork, and their loss is the main pathological reason for glaucoma. The present study was to investigate mechanisms that regulate RGCs survival.

Methods: A mouse model of glaucoma was established by injecting hypertonic saline into the limbal veins. RGCs apoptosis was detected by using flow cytometry. Protein expressions in RGCs in response to DNA damage inducer cisplatin treatment were detected by immunofluorescence and western blot. The expressions of inflammatory cytokines were determined using ELISA and real-time PCR.

Results: In the hypertonic saline-injected mice, we found visual function was impaired followed by the increased expression of γH2AX and activation of cGAS-STING signaling. We found that DNA damage inducer cisplatin treatment incurred significant DNA damage, cell apoptosis, and inflammatory response. Mechanistically, cisplatin treatment triggered activation of the cGAS-STING signaling by disrupting mitochondrial function. Suppression of cGAS-STING ameliorated inflammation and protected visual function in glaucoma mice.

Conclusions: The data demonstrated that cGAS-STING signaling is activated in the damaged retinal ganglion cells, which is associated with increased inflammatory responses, DNA damage, and mitochondrial dysfunction. Targeting the cGAS-STING signaling pathway represents a potential way to alleviate glaucoma-related visual function.