ATF3 prevents retinal ganglion cell apoptosis and mitigates microglia-mediated neuroinflammation in retinal ischemia-reperfusion injury.

Introduction: Neuroinflammation is a key pathological response involved in secondary optic nerve injury following retinal ischemia-reperfusion injury. The expression of activating transcription factor 3 (ATF3), a highly conserved protein, is rapidly induced post-injury and is crucial for regulating immunity and inflammation. The potential neuroprotective mechanisms, function, and therapeutic potential of ATF3 following retinal ischemia-reperfusion remain largely unexplored. In this study, we examined the expression and distribution of ATF3 and achieved the overexpression of ATF3 in mouse retina via injection of adeno-associated virus vectors. Methods: Retinal ganglion cell survival was assessed using immunofluorescence staining and terminal deoxynucleotidyl transferase dUTP nick-end labeling assay. Activation status and polarization of microglia and microglia-associated neuroinflammation were also evaluated. In addition, peripheral venous blood samples and aqueous humor were collected from 20 individuals, 10 patients with primary angle-closure glaucoma and 10 controls, to detect changes in ATF3 expression. Results: ATF3 overexpression partially suppressed retinal ganglion cell apoptosis by activating the p-Akt pathway, inhibited microglial activation, reversed microglial M1/M2 polarization, and reduced the release of inflammatory factors by decreasing integrin CD11b expression. ATF3 overexpression improved retinal structure and function by regulating microglial behavior and decreased neuronal death post-retinal ischemia-reperfusion. Discussion: ATF3 overexpression may be a potential therapeutic strategy for the management of retinal ischemia-reperfusion-associated neurodegenerative diseases.