Aberrant STING signalling promotes endothelial dysfunction and neurovascular injury in diabetic retinopathy

Diabetic retinopathy is a common complication of diabetes mellitus that is characterised by neurovascular dysfunction and chronic inflammation. The stimulator of IFN genes (STING) signalling pathway plays a key role in inflammatory diseases. However, its cell-specific function and value as an early-intervention target for diabetic retinopathy remain unclear.

We analysed public single-cell (sc)RNA-seq datasets from fibrous membranes of individuals with proliferative diabetic retinopathy and idiopathic macular hole, normal post-mortem retinas and retinal endothelial cells from diabetic and non-diabetic mice. A type 2 diabetes mouse model was established using a high-fat diet and streptozocin to assess STING localisation and expression differences. Using adeno-associated virus (serotype 2/1), siRNA or STING inhibitor H-151, we evaluated the effects of STING on inflammation and cell function both in vivo and in vitro.

scRNA-seq analysis revealed increased STING expression and enriched IFN signalling in endothelial cells from samples of both humans and mice with diabetes. Our mouse model exhibited increased STING expression, along with its co-localisation with CD31, and upregulated IFNs in retinal tissues. Flow cytometry confirmed diabetes-induced endothelial cell-specific phosphorylation of TBK1, a downstream effector of STING. Genetic deletion or pharmacological inhibition of STING significantly ameliorated retinal inflammation and neurovascular dysfunction in diabetic mice.

Our findings demonstrate endothelial-intrinsic activation of the cyclic GMP-AMP synthase (cGAS)/STING/IFN pathway as a key driver of retinal inflammation and neurovascular dysfunction in diabetes. Targeting this pathway may offer a potential therapeutic approach for early intervention in diabetic retinopathy.