STING immune activation of microglia aggravating neurovascular unit damage in diabetic retinopathy

Diabetic retinopathy (DR) is the leading cause of blindness and is pathologically characterized by neuroinflammation and neovascularization. Retinal homeostasis is critically maintained by the retinal neurovascular unit (NVU), which can be disrupted by abnormal activation of microglia in DR. However, the underlying mechanism remains unclear. Here, we provide the first evidence of upregulated stimulator of interferon genes (STING) in microglia within fibrovascular membranes (FVMs) and retinas from oxygen-induced retinopathy (OIR) and streptozotocin (STZ)-induced diabetic mice. Furthermore, we identified STING upregulation in BV2 cells stimulated with high glucose (HG) or hypoxia, accompanied by mitochondrial dysfunction and cytoplasmic leakage of damaged mitochondrial DNA (mtDNA). Pharmacologic or genetic inhibition of STING in microglia prevented their activation and polarization. Next, we demonstrated that STING-deficient BV2 cells reversed the proangiogenic behavior of endothelial cells and protected retinal ganglion cells (RGCs) from oxidative stress. Finally, intravitreal injection of AAV-STING alleviated retinal neurovascular pathologies in both OIR and STZ mice. This study demonstrated that the release of mtDNA mediates STING immune activation of microglia, which further exacerbates NVU damage in DR. In contrast, immunosuppressing STING in microglia could serve as a potential therapeutic strategy. • Microglia mitochondrial dysfunction mediates the release of mtDNA thereby activating STING and its downstream pathways. • Pharmacological inhibition or genetic suppression of STING in microglia significantly ameliorates retinal neurovascular pathologies in diabetic rodent retina. • Inhibiting STING immune activation may serve as a potential therapeutic strategy for DR.