The STING pathway: An uncharacterized angle beneath the gut–retina axis

The gut-retina axis is an emerging concept that describes a close interaction between the gut host-microbiota interface and the retina. Stimulator of interferon genes (STING) is a universally expressed adaptor protein localized in the endoplasmic reticulum. When activated by the cytosolic DNA sensor cyclic GMP-AMP synthase (cGAS), STING induces the activation of the transcription factor interferon regulatory factor 3 (IRF3) and nuclear factor-κB (NF-κB). Downstream effects include inflammation, autophagy, and programmed cell death. Dysregulation of the STING pathway has emerged as a crucial pathogenic mechanism underpinning a broad range of inflammatory diseases, autoimmune diseases, and cancer. Recently, a positive feedback loop between dysbiosis and aberrant activation of the intestinal STING pathway has been demonstrated, concurrently related to increased intestinal permeability. Alternations in the STING pathway have also been reported in the retina of patients with ocular diseases and retinal cells treated with pathological stimuli. Collectively, there is a chance that dysbiosis in patients with retinal diseases disrupts intestinal homeostasis and exacerbates barrier dysfunction through the erroneous accumulation of STING in the gut. Subsequent translocation of microbial products into the bloodstream allows access to the eye via the impaired blood-retina barrier, inducing the chronic activation of the STING pathway in the retina to participate in the disease progression. In this review, we explore how the alterations in the STING pathway could contribute to the gut disturbance and retinal pathologies and discuss its potential as a therapeutic target to treat the gut-retina axis-related diseases, which sheds some light on the better understanding of the crosstalk between the gut and retina.