Emerging Roles of cGAS-STING Signaling in Mediating Ocular Inflammation

Abstract

Cyclic GMP-AMP (cGAMP) synthase (cGAS), a sensor of cytosolic DNA, recognizes cytoplasmic nucleic acids to activate the innate immune responses via generation of the second messenger cGAMP and subsequent activation of the stimulator of interferon genes (STINGs). The cGAS-STING signaling has multiple immunologic and physiological functions in all human vital organs. It mediates protective innate immune defense against DNA-containing pathogen infection, confers intrinsic antitumor immunity via detecting tumor-derived DNA, and gives rise to autoimmune and inflammatory diseases upon aberrant activation by cytosolic leakage of self-genomic and mitochondrial DNA. Disruptions in these functions are associated with the pathophysiology of various immunologic and neurodegenerative diseases. Recent evidence indicates important roles of the cGAS-STING signaling in mediating inflammatory responses in ocular inflammatory and inflammation-associated diseases, such as keratitis, diabetic retinopathy, age-related macular degeneration, and uveitis. In this review, we summarize the recently emerging evidence of cGAS-STING signaling in mediating ocular inflammatory responses and affecting pathogenesis of these complex eye diseases. We attempt to provide insightful perspectives on future directions of investigating cGAS-STING signaling in ocular inflammation. Understanding how cGAS-STING signaling is modulated to mediate ocular inflammatory responses would allow future development of novel therapeutic strategies to treat ocular inflammation and autoimmunity.

Keywords: Age-related macular degeneration; Diabetic retinopathy; Keratitis; Ocular inflammation; Uveitis; cGAS-STING signaling.

Fig. 1.

The cGAS-STING signaling pathway senses cytoplasmic DNA and triggers innate immune responses to mediate ocular inflammation. The presence of cytosolic DNA, either as foreign DNA from HSV-1 DNA viruses and A. fumigatus or as self-DNA from damaged mitochondria is recognized by cGAS. Binding of cGAS to the cytosolic DNA leads to the formation of cGAS-DNA complexes, where cGAS is activated and catalyzes the synthesis of cGAMP, a potent ligand of STING. cGAMP binds to and activates STING. The activated STING subsequently recruits and activates TBK1 and IKK. The activated TBK1 and IKK in turn phosphorylate IRF3 and the transcription factor NF-κB, respectively. The phosphorylated IRF3 dimerizes and translocates into the nucleus while the phosphorylated NF-κB also enters the nucleus. Dimerized phosphorylated IRF3 together with NF-κB in the nucleus turns on the expression of interferons (IFNs) and other inflammatory cytokines, such as TNF, IL-1β, IL-6, and IL-18, to mediate ocular inflammation.

Fig. 2.

Summary of the emerging roles of cGAS-STING signaling in ocular inflammation. In infectious keratitis, pathogens including fungi and HSV trigger cGAS-STING signaling-mediated innate immune responses to contain pathogenic infection and HSV replication in cornea. In DR, high glucose exposure and other pathological stimuli result in mitochondrial stress and cytosolic mtDNA leakage in retinal vascular endothelial cells and photoreceptors, which subsequently lead to BRB breakdown and photoreceptor dysfunction. In neovascular AMD, oxidative stress in RPE gives rise to DNA damage, which activates cGAS-STING signaling to promote the production of VEGF via NF-κB/HIF-1α and contribute to pathological angiogenesis. In non-neovascular AMD, DICER1 deficit, oxidative stress, and LCN2 upregulation lead to cGAS-STING signaling activation and subsequent inflammation to contribute to RPE degeneration and death of photoreceptors. DICER1 deficit results in accumulation of Alu RNA, which is subsequently reverse transcribed into Alu cDNA by long interspersed nuclear element-1 reverse transcriptase (L1RT). The accumulation of Alu cDNA leads to reactive oxygen species (ROS) in mitochondria and mtDNA leakage into cytosol from the damaged mitochondria, which activates cGAS-STING signaling and promotes inflammasome formation to contribute to RPE degeneration. Oxidative stress in RPE promotes chromatin decondensation in gene loci of cGAS and STING, which enhances cGAS-STING signaling activation and inflammation under oxidative stress to exacerbate RPE degeneration and photoreceptor death. LCN2 upregulation also leads to cGAS-STING signaling activation and subsequent inflammation to promote RPE degeneration.