Microglial cGAS-STING signaling underlies glaucoma pathogenesis.

Area of Science:

• Neuroscience
• Immunology
• Ophthalmology

Background:

• Glaucoma causes irreversible blindness by damaging retinal ganglion cells (RGCs).
• The precise mechanisms driving RGC loss in glaucoma remain unclear.
• Glaucoma affects over 78 million people globally, with no cure.

Purpose of the Study:

• To investigate the role of cGAS-STING signaling in glaucoma pathogenesis.
• To explore potential therapeutic targets within the cGAS-STING pathway for glaucoma treatment.

Main Methods:

• Utilized distinct murine models of glaucoma.
• Assessed the impact of global and microglial STING deletion on glaucoma.
• Examined the effects of genetic cGAS-STING supersensitivity.
• Investigated therapeutic interventions targeting cGAS-STING signaling (TBK1i, anti-IFNAR1 antibody).

Main Results:

• cGAS-STING signaling was activated in retinal microglia during glaucoma.
• STING deletion ameliorated glaucoma symptoms, protecting RGCs and vision.
• Genetic cGAS-STING supersensitivity worsened neuroinflammation and RGC loss.
• Targeting cGAS-STING signaling prevented glaucoma-induced RGC and vision loss.

Conclusions:

• cGAS-STING signaling plays a critical role in glaucoma pathogenesis.
• Microglial cGAS-STING activation drives RGC apoptosis via neuroinflammation.
• Targeting cGAS-STING represents a promising therapeutic strategy for glaucoma.