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-1β induces rod photoreceptor cell death during experimental subretinal inflammation and in retinal explants exposed to IL-1β but the mechanism is unknown. METHODS Retinal explants were culture in the presence of human monocytes or IL-1β 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-1β. Glutamate receptor antagonists were evaluated for their ability to reduce photoreceptor cell death in the presence of IL1-β or monocytes. RESULTS We here show that IL-1β does not induce death in isolated photoreceptors, suggesting an indirect effect. We demonstrate that IL-1β 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 Müller cells, increased release from Müller 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-1β 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-1β-induced rod degeneration.

中文翻译：

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IL-1β通过破坏视网膜谷氨酸稳态来诱导杆变性。

背景技术与年龄有关的黄斑变性的特征在于视网膜下巨噬细胞的积累和视锥，但主要是视杆的退化。先前我们已经证明，单核吞噬细胞衍生的IL-1β在实验性视网膜下炎症和暴露于IL-1β的视网膜外植体中诱导视杆光感受器细胞死亡，但机制尚不清楚。方法在人单核细胞或IL-1β存在下培养视网膜外植体，并通过TUNEL标记分析感光细胞的存活。在IL-1β存在或不存在的情况下，对培养的外植体细胞级分中谷氨酸的稳态水平相关基因的谷氨酸浓度和转录水平进行了分析。评估谷氨酸受体拮抗剂在IL1-β或单核细胞存在下减少感光细胞死亡的能力。结果我们在这里显示IL-1β不会在孤立的感光器中诱导死亡，这表明是间接作用。我们证明，IL-1β会导致谷氨酸诱导的杆状感光细胞死亡，因为它通过抑制Müller细胞向谷氨酰胺的转化，增加Müller细胞的释放以及减少再摄取而增加了视网膜中细胞外谷氨酸的浓度。非NMDA受体的抑制作用完全有效地防止了在存在IL-1β的情况下（或更重要的是在体内）视网膜下炎症模型培养的视网膜外植体中杆的凋亡。结论我们的研究强调了炎症在解除谷氨酸稳态过程中的重要性，并为IL-1β诱导的棒变性提供了全面的作用机制。