Rôle de l'interleukine - 1 bêta dans la dégénérescence des photorécepteurs associée à la dégénérescence maculaire liée à l'âge

Abstract : In geographic atrophy (GA), one of the late forms of Age-related Macular Degeneration (AMD), an extending atrophic zone forms, characterized by the loss of retinal pigment epithelium and photoreceptor degeneration. Subretinal mononuclear phagocytes (MPs) accumulate in GA, and are associated with IL-1β-dependent retinal degeneration. First, we confirmed that subretinal accumulation of MPs is associated with rod degeneration and cone segment loss in the transitional zone in GA human samples. Using ex vivo and in vivo models, we then demonstrated that MPs-derived IL-1β leads to severe cone segment degeneration. Therefore, inhibiting subretinal MP accumulation or IL-1β might protect the cone segment, and help preserve high acuity daytime vision in conditions characterized by subretinal inflammation. Second, we showed that IL-1β effect on rod degeneration is indirect, and mediated by glutamate. Our results indicate that IL-1β impairs Müller glial cells glutamate recycling, and subsequently leads to the extracellular increase in glutamate content. Inhibiting glutamate receptors to prevent excitotoxicity, or exogenous cystine supplementation to supply antioxidant metabolism, are sufficient to protect rods from IL-1β-induced neurotoxicity. Our results provide new perspectives to treat pathologies associated with subretinal inflammation such as late AMD. Our results collectively demonstrated that MP-derived IL-1β induces cone segment loss, and glutamate homeostasis disruption associated with rod degeneration. This study will help with the development of new therapeutic strategies in dealing with inflammatory retinal pathologies as geographic atrophy.
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Hugo Charles-Messance. Rôle de l'interleukine - 1 bêta dans la dégénérescence des photorécepteurs associée à la dégénérescence maculaire liée à l'âge. Physiologie [q-bio.TO]. Sorbonne Université, 2018. Français. ⟨NNT : 2018SORUS047⟩. ⟨tel-02132148⟩

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