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

Severe, early-onset photoreceptor (PR) degeneration associated with MERTK mutations is thought to result from failed phagocytosis by retinal pigment epithelium (RPE). Notwithstanding, the severity and onset of PR degen-eration in mouse models of Mertk ablation are determined by the hypomorphic expression or the loss of the Mertk paralog Tyro3. Here, we find that loss of Mertk and reduced expression/loss of Tyro3 led to RPE inflamma-tion even before eye-opening. Incipient RPE inflammation cascaded to involve microglia activation and PR de-generation with monocyte infiltration. Inhibition of RPE inflammation with the JAK1/2 inhibitor ruxolitinib mitigated PR degeneration in Mertk-/- mice. Neither inflammation nor severe, early-onset PR degeneration was observed in mice with defective phagocytosis alone. Thus, inflammation drives severe, early-onset PR de-generation-associated with Mertk loss of function.

Automated summary

Severe, early-onset photoreceptor degeneration associated with MERTK mutations is caused by failed phagocytosis by retinal pigment epithelium. However, the severity and onset of PR degeneration in mouse models are determined by the expression of Mertk paralog Tyro3. Loss of Mertk and reduced Tyro3 expression led to RPE inflammation before eye-opening, which further activated microglia and caused PR degeneration with monocyte infiltration. Inhibition of RPE inflammation with the JAK1/2 inhibitor ruxolitinib mitigated PR degeneration. Therefore, inflammation plays a crucial role in severe, early-onset PR degeneration associated with Mertk loss of function.