Heterochromatin inhibits cGAS and STING during oxidative stress-induced retinal pigment epithelium and retina degeneration

Age-related macular degeneration (AMD) is a leading cause of blindness characterized by degeneration of retina pigment epithelium (RPE) and photoreceptors in the macular region. Activation of the innate immune cGASSTING signaling has been detected in RPE of dry AMD patients, but the regulatory basis is largely unexplored. Heterochromatin is a highly compact, transcription inert chromatin status. We have recently shown that heterochromatin is required for RPE survival through epigenetically silencing p53-mediated apoptosis signaling. Here, we found that cGAS and STING were dose-dependently upregulated in mouse RPE and retina during oxidative injury, correlated with decreased chromatin compaction in their gene loci. Genetic or pharmaceutical disruption of heterochromatin leads to elevated cGAS and STING expression and enhanced inflammatory response in oxidative stress-induced RPE and retina degeneration. In contrast, application of methotrexate (MTX), a recently identified heterochromatin-promoting drug, inhibits cGAS and STING in both RPE and retina, attenuates RPE/retina degeneration and inflammation. Further, we show that intact heterochromatin is required for MTX to repress cGAS and STING. Together, we demonstrated an unrevealed regulatory function of heterochromatin on cGAS and STING expression and provide potential new therapeutic strategy for AMD treatment.

Automated summary

The study found that cGAS and STING were upregulated in mouse RPE and retina during oxidative injury, correlated with decreased chromatin compaction in their gene loci. Disruption of heterochromatin led to elevated cGAS and STING expression and enhanced inflammatory response in oxidative stress-induced RPE and retina degeneration. Application of methotrexate (MTX), a heterochromatin-promoting drug, inhibited cGAS and STING expression, attenuating RPE/retina degeneration and inflammation.