P2Y6R-positive microglia sense the stress metabolite uridine and exacerbate photoreceptor degeneration in the retina

Retinitis pigmentosa (RP) is an incurable blinding disorder characterized by progressive photoreceptor degeneration. While metabolic stress has been implicated in RP progression, the neuroimmune mechanisms driving this process remain poorly understood. In this study, we employed time-series untargeted metabolomics to profile temporal metabolic changes during RP pathogenesis using the retinal degeneration 10 (rd10) mouse model, identifying uridine as a key metabolite dynamically associated with disease progression. Intravitreal uridine administration in wild-type C57BL/6J mice induced RP-like pathology, including photoreceptor apoptosis and visual impairment, alongside aberrant microglial activation. Microglial depletion reversed these degenerative phenotypes, implicating microglia as central mediators of uridine-driven neurodegeneration. Further analysis revealed that uridine-reactive microglia adopted a pro-inflammatory state and aberrantly phagocytosed viable photoreceptors. Single-cell RNA sequencing (scRNA-seq) of rd10 retinas uncovered a distinct P2Y6R-expressing microglial subpopulation with a dual phenotype characterized by both proinflammatory and phagocytic activity. In vitro studies confirmed that uridine activates microglia via P2Y6R signaling, triggering both inflammatory cytokine release and dysregulated phagocytosis—effects that are abolished by P2Y6R inhibition. Our findings identify the uridine-P2Y6R axis as a novel metabolic-immune checkpoint in RP, orchestrating microglia-mediated photoreceptor degeneration. Targeting this axis presents a promising therapeutic strategy for RP.