Inflammation of the retinal pigment epithelium drives early-onset photoreceptor degeneration in <i>Mertk</i>-associated retinitis pigmentosa.

Abstract

Severe, early-onset photoreceptor (PR) degeneration associated with <i>MERTK</i> 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 <i>Mertk</i> ablation are determined by the hypomorphic expression or the loss of the <i>Mertk</i> paralog <i>Tyro3</i>. Here, we find that loss of <i>Mertk</i> and reduced expression/loss of <i>Tyro3</i> 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 <i>Mertk</i>^-/- 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 <i>Mertk</i> loss of function.