Retinal pigment epithelium-derived PD-L1 reprograms microglial cells and protects against retinal degeneration in mouse models of experimental AMD and genetic retinitis pigmentosa

Retinal degeneration is a leading cause of blindness and a significant health burden during aging worldwide. Because of its complex pathogenic mechanisms, however, effective interventions applicable to multiple retinal degenerations remain limited. Excessive microglia-mediated inflammation is a common pathological feature of different retinal degenerative diseases, and inhibiting these overactive inflammatory responses by reprogramming microglia may provide a therapeutic strategy with broad-spectrum potential. Here, we uncover a novel retinal pigment epithelium (RPE) homeostatic signal, PD-L1, that drives the reprogramming of activated microglial toward a retinal-protective phenotype. Using multiple analyses, including gene expression profiling bioinformatics, adeno-associated virus-mediated RPE-specific gene overexpression, pharmacological, and genetic manipulations, we show that RPE cells upregulate the expression of PD-L1 to modulate microglia for protection against retinal degeneration in an experimental dry AMD mouse model. Bioinformatics enrichment analysis of the high-expression gene signatures of subretinal microglia in AMD patients, combined with pharmacological blocking of NF-κB activity or using Nlrp3 knockout mice, show that PD-L1/PD-1 signaling suppresses NF-κB activation in microglia, thereby inhibiting NLRP3 inflammasome priming and attenuating microglia-mediated excessive inflammation. Furthermore, the overexpression of PD-L1 by the AAV8 virus exerts similar microglial reprogramming and retinal protective effects to alleviate retinal degeneration in a preclinical model of retinitis pigmentosa. These findings reveal that RPE-derived PD-L1 suppresses inflammatory reprogramming of subretinal microglia and mitigates retinal degeneration, highlighting a promising proof of concept for PD-L1 as a potential therapeutic target for the broad treatment of retinal degenerative diseases.