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

Maria E MercauYemsratch T AkaluFrancesca MazzoniGavin GyimesiEmily J AlbertoYong KongBrian P HaflerSilvia C FinnemannCarla V RothlinSourav Ghosh
Published in: Science advances (2023)
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 degeneration 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 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 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 degeneration-associated with Mertk loss of function.
Keyphrases
  • early onset
  • late onset
  • oxidative stress
  • poor prognosis
  • inflammatory response
  • mouse model
  • spinal cord injury
  • spinal cord
  • atrial fibrillation
  • skeletal muscle
  • neuropathic pain
  • peripheral blood
  • insulin resistance