IL-1 beta induces rod degeneration through the disruption of retinal glutamate homeostasis

Charles-Messance, Hugo; Blot, Guillaume; Couturier, Aude; Vignaud, Lucile; Touhami, Sara; Beguier, Fanny; Siqueiros, Lourdes; Forster, Valerie; Barmo, Nour; Augustin, Sebastien; Picaud, Serge; Sahel, Jose-Alain; Rendon, Alvaro; Grosche, Antje; Tadayoni, Ramin; Sennlaub, Florian und Guillonneau, Xavier (2020): IL-1 beta induces rod degeneration through the disruption of retinal glutamate homeostasis. In: Journal of Neuroinflammation, Bd. 17, Nr. 1, 1

Abstract

Background: Age-related macular degeneration is characterized by the accumulation of subretinal macrophages and the degeneration of cones, but mainly of rods. We have previously shown that Mononuclear Phagocytes-derived IL-1 beta induces rod photoreceptor cell death during experimental subretinal inflammation and in retinal explants exposed to IL-1 beta but the mechanism is unknown. Methods Retinal explants were culture in the presence of human monocytes or IL-1 beta and photoreceptor cell survival was analyzed by TUNEL labeling. Glutamate concentration and transcription levels of gene involved in the homeostasis of glutamate were analyzed in cell fractions of explant cultured or not in the presence of IL-1 beta. Glutamate receptor antagonists were evaluated for their ability to reduce photoreceptor cell death in the presence of IL1-beta or monocytes. Results We here show that IL-1 beta does not induce death in isolated photoreceptors, suggesting an indirect effect. We demonstrate that IL-1 beta leads to glutamate-induced rod photoreceptor cell death as it increases the extracellular glutamate concentrations in the retina through the inhibition of its conversion to glutamine in Muller cells, increased release from Muller cells, and diminished reuptake. The inhibition of non-NMDA receptors completely and efficiently prevented rod apoptosis in retinal explants cultured in the presence of IL-1 beta or, more importantly, in vivo, in a model of subretinal inflammation. Conclusions: Our study emphasizes the importance of inflammation in the deregulation of glutamate homeostasis and provides a comprehensive mechanism of action for IL-1 beta-induced rod degeneration.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Sprache: Englisch