The cGAS-STING pathway in diabetic retinopathy and age-related macular degeneration

Abstract

Diabetic retinopathy and age-related macular degeneration are common retinal diseases with shared pathophysiology, including oxidative stress-induced inflammation. Cellular mechanisms responsible for converting oxidative stress into retinal damage are ill-defined but have begun to clarify. One common outcome of retinal oxidative stress is mitochondrial damage and subsequent release of mitochondrial DNA into the cytosol. This leads to activation of the cGAS-STING pathway, resulting in interferon release and disease-amplifying inflammation. This review summarizes the evolving link between aberrant cGAS-STING signaling and inflammation in common retinal diseases and provides prospective for targeting this system in diabetic retinopathy and age-related macular degeneration. Further defining the roles of this system in the retina is expected to reveal new disease pathology and novel therapeutic approaches.

Keywords: age-related macular degeneration; cGAS–STING; cytokine release; diabetic retinopathy; inflammasome activation; inflammation; innate immune response; oxidative stress; retinal damage.

Figure 1.. Structure of the 2:2 cGAS/DNA complex.

Each monomer contains two visualized DNA-binding sites, site-A and site-B. The right-side monomer is depicted with ATP and Mg²⁺ in the catalytic site. The Zn²⁺ cofactor is colored dark green and occupies space near the DNA backbone. More recently, site-C was also discovered to have DNA-binding activity. The unstructured N-terminal domain is theorized to provide yet another DNA-binding site. Activity of the NTD and site-C are required for formation of cGAS condensates. (PDB: 4LEZ).

Figure 2.. Superposition of STING apoenzyme (red) and STING holoenzyme (green).

Activation of STING by 2,3-cGAMP leads to significant conformational changes, including a 15° inward rotation of the ligand-binding domain and the formation of a lid above the cyclic dinucleotide binding pocket from unstructured loops in the apo state. STING apoenzyme (PDB: 6NT5); STING holoenzyme (PDB: 7SII). RMSD = 5.386 Å PDB: Protein Data Bank; RMSD: Root mean square deviation.

Figure 3.. Attributes of cGAS-STING signaling.

(A) Key interactions of the cGAS-STING pathway with ROS and hyperglycemia. ROS plays a central role, contributing to mitochondrial dysfunction, upregulation of cGAS and STING, and inhibition of TREX1, resulting in production of interferon and activation of NF-κB. Expression of type I interferons and cytokines result in the central pathophysiologies of DR and AMD: angiogenesis and complement activation. (B) The downstream effects of aberrant cGAS-STING signaling leads to recruitment and activation of immune cells and prolonged oxidative stress. These mechanisms drive several pathological changes in the retina and retinal vasculature, leading to retinal dysfunction, hemorrhage, and edema that can cause vision loss. AGE: Advanced glycation endproduct; AMD: Age-related macular degeneration; DR: Diabetic retinopathy; ROS: Reactive oxygen species.

Figure 4.. Current state of cGAS-STING/retina interplay.

The cGAS-STING pathway is considered to be a key effector for several pathologies that drive vision loss in inflammatory retinal disease. Chronic exposure to inflammatory inputs drives the activation of the immune system and the degeneration of retinal cells. PPARα: Peroxisome proliferator-activated receptor alpha.