The Pathogenic Role of cGAS-STING Signaling in Diabetic Retinopathy

Abstract

Purpose : Dysregulated immune response to diabetic stress is a key trigger of diabetic retinopathy (DR) in patients and animal models, leading to retinal neuronal degeneration and vasculopathy. Fine-tuning innate immunity is a promising direction to uncover therapeutic targets of DR. In this study, we investigated the role of a fundamental inflammatory regulator, cGAS-STING signaling, in neuronal function and vasculopathy of type I diabetic models.

Methods : The protein levels of cGAS-STING signaling were measured by Western blot analysis in retinas of type I diabetic models, including streptozotocin(STZ)-induced diabetic C57BL/6J mice and Ins2^Akita/J mice. Age-matched WT mice and cGas^-/- mice with or without STZ-induced diabetes were used to investigate: 1) retinal neuronal degeneration measured by Electroretinogram (ERG) and optical coherence tomography (OCT), 2) retinal vasculopathy including leukostasis, vascular leakage, and endothelial apoptosis. Cellularly, to identify the source of inflammation, cGAS-STING signaling and cytosolic double-strand DNA were measured in peripheral blood mononuclear cells (PBMCs) of STZ-induced diabetes. Mechanically, Pparα^-/- mice and PPARα agonist-treated mice were applied to test if PPARα serves as the upstream of cGAS-STING signaling.

Results : cGAS-STING signaling was upregulated in the retinas of both diabetic models. Disruption of cGAS-STING signaling by the knockout (KO) of cGas ameliorated ERG decline and reduction of retinal thickness in the STZ diabetic model. cGas KO reduced the leukocyte adhesion to retinal vasculature, suppressed albumin leakage, and decreased the percentage of propidium iodide-positive endothelial cells (PI⁺CD31⁺) in diabetic retinas. Aberrant upregulation of cGAS-STING signaling and increased cytosolic mitochondrial DNA (mtDNA) was correlated with the downregulation of PPARα in diabetic PBMCs. Pparα KO increased while fenofibrotic acid (PPARα agonist) decreased cGAS-STING signaling. In addition, RU.521 (cGAS inhibitor) suppressed diabetic stressor-induced pro-inflammatory cytokines in human retinal capillary endothelial cells.

Conclusions : Overactivated cGAS-STING signaling played a pathogenic role in DR by promoting vasculopathy and neuronal degeneration and represents a promising therapeutic target. Cell-specific research is warranted to delicately dissect the role of cGAS-STING signaling in retinal neurons, vasculature, and immune cells of DR in the future.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.