Blocking cGAS-STING Inflammatory Signaling Protects the Retina from Glaucoma
Researchers here provide evidence for retinal degeneration to be driven in part by maladaptive innate immune signaling running through the cGAS-STING pathway. This pathway is the target of a fair amount of research these days, as the research community is interested in finding novel ways to effectively interfere in the chronic inflammation that is characteristic of aging and many forms of degenerative disease. As always seems to be the case, the challenge is that unwanted, harmful inflammatory signaling uses the same mechanisms as the desirable, short-term inflammatory signaling that is necessary to the function of the immune system. A viable, useful way to distinguish between these two has yet to emerge.
Glaucoma is a kind of progressive optic neurodegeneration characterized by elevated intraocular pressure (IOP), severe eye pain, and irreversible vision loss that could lead to the progress of permanent blindness. Retinal ganglion cells (RGCs) are the neurons that convey visual information and their loss ultimately causes deficits in neuronal function, which is considered the main pathological hallmark of glaucoma. The loss of RGCs is triggered by multiple mechanisms, such as neurotrophic factor deprivation, axonal transport failure, activation of apoptotic signals, mitochondrial dysfunction, oxidative stress, and loss of synaptic connectivity, etc.
It is now confirmed that cellular injuries induced by aging or ischemia can cause unbalanced oxidative stress in mitochondria by producing uncontrolled levels of ROS, leading to severe cell death. DNA damage is involved in RGCs loss by mediating aging, oxidative stress, post-mitotic neurons, as well as glutamate excitotoxicity, and is considered the major form of neurological disorder. Therefore, strategies that halt and repair DNA damage are recognized to be beneficial for reducing RGCs loss in glaucoma.
It is believed that DNA damage is regulated by several mechanisms, such as protein modification and signaling pathway dysfunction. The cGAS-STING pathway is associated with DNA damage sensing, modulation of inflammatory responses, autoimmunity, and cellular senescence. Previous studies showed that inhibition of the cGAS-STING pathway exhibited potential alleviating effects on ischemia/reperfusion injury-induced retinal ganglion cell death. Moreover, diverse effects of the cGAS-STING signaling have been found in mediating ocular diseases including age-related macular degeneration, keratitis, diabetes mellitus, and uveitis. In the present study, we aimed to explore the potential mechanism underlying RGCs loss in glaucoma and the contribution of cGAS/STING signaling to the loss of RGCs in response to DNA stress.
A mouse model of glaucoma was established by injecting hypertonic saline into the limbal veins. In the hypertonic saline-injected mice, we found visual function was impaired followed by the increased expression of γH2AX, a DNA damage marker, and activation of cGAS-STING signaling. We found that DNA damage inducer cisplatin treatment incurred significant DNA damage, cell apoptosis, and inflammatory response. Mechanistically, cisplatin treatment triggered activation of the cGAS-STING signaling by disrupting mitochondrial function. Suppression of cGAS-STING ameliorated inflammation and protected visual function in glaucoma mice. Thus targeting cGAS-STING signaling represents a potential therapeutic strategy for glaucoma.