OGG1 modulates the crosstalk of microglia and Müller cells in degenerative retinas via alleviating inflammatory response and oxidative stress.

Abstract

Oxidative stress and neuroglial-driven inflammation are crucial in the pathogenesis of retinal degeneration (RD). 8-hydroxyguanine DNA glycosylase 1 (OGG1), a key enzyme in repairing oxidative DNA damage via the base excision repair (BER) pathway, also regulates inflammatory responses. Using the sodium iodate (NaIO)-induced oxidative stress model in C57BL/6J mice, we investigated the temporal dynamics of OGG1 expression and its functional role in RD. To specifically inhibit OGG1 activity, TH5487 - a potent and highly selective OGG1 inhibitor-was administered via intravitreal injection, rapidly and reversibly creating a functional OGG1-deficient state. We observed a significant initial upregulation of OGG1 at the onset of RD, followed by a rapid decline as photoreceptor degeneration progressed. OGG1 deficiency exacerbated DNA oxidative damage and impaired its repair capacity. Immunostaining revealed pronounced neuroglial activation in RD retinas, with microglial activation preceding Müller cell gliosis. Intravitreal delivery of exogenous OGG1 suppressed neuroglial activation, mitigated photoreceptor loss, and partially restored electroretinogram (ERG) responses. These protective effects were reversed by co-administration of OGG1+TH5487. In vitro assays demonstrated that OGG1 alleviates oxidative stress, preserved mitochondrial integrity in microglia, and subsequently modulated the gliotic response of Müller cells. Mechanistically, OGG1 deficiency accelerates RD progression by disrupting oxidative damage repair and amplifying neuroinflammatory cascades. Conversely, OGG1 supplementation coordinates retinal protection through a dual mechanism: directly repairing oxidative DNA lesions and indirectly modulation of the neuroinflammatory microenvironment by suppressing microglia-driven inflammation and Müller cell gliosis. These findings establish OGG1 as a central regulator linking oxidative DNA damage to neuroglial dysfunction in RD. Clinically, targeted OGG1 delivery represents a promising therapeutic strategy for degenerative retinopathies by concurrently addressing oxidative injury and neuroinflammation.