Inflammation of the retinal pigment epithelium drives early-onset photoreceptor degeneration in Mertk -associated retinitis pigmentosa

Severe, early-onset photoreceptor (PR) degeneration associated with mutations is thought to result from failed phagocytosis by retinal pigment epithelium (RPE). Notwithstanding, the severity and onset of PR degeneration in mouse models of ablation are determined by the hypomorphic expression or the loss of the paralog . Here, we find that loss of and reduced expression/loss of led to RPE inflammation even before eye-opening. Incipient RPE inflammation cascaded to involve microglia activation and PR degeneration with monocyte infiltration. Inhibition of RPE inflammation with the JAK1/2 inhibitor ruxolitinib mitigated PR degeneration in mice. Neither inflammation nor severe, early-onset PR degeneration was observed in mice with defective phagocytosis alone. Thus, inflammation drives severe, early-onset PR degeneration-associated with loss of function.