Rhegmatogenous retinal detachment (RD) involving the macula is a major cause of visual impairment despite high surgical success rate, mainly because of cone death. RD causes the infiltration of activated immune cells, but it is not clear whether and how infiltrating inflammatory cells contribute to cone cell loss. Vitreous samples from patients with RD and from control patients with macular hole were analyzed to characterize the inflammatory response to RD. A mouse model of RD and retinal explants culture were then used to explore the mechanisms leading to cone death. Analysis of vitreous samples confirms that RD induces a marked inflammatory response with increased cytokine and chemokine expression in humans, which is closely mimicked by experimental murine RD. In this model, we corroborate that myeloid cells and T-lymphocytes contribute to cone loss, as the inhibition of their accumulation by Thrombospondin 1 (TSP1) increased cone survival. Using monocyte/retinal co-cultures and TSP1 treatment in RD, we demonstrate that immune cell infiltration downregulates rod-derived cone viability factor (RdCVF), which physiologically regulates glucose uptake in cones. Insulin and the insulin sensitizers rosiglitazone and metformin prevent in part the RD-induced cone loss in vivo, despite the persistence of inflammation Our results describe a new mechanism by which inflammation induces cone death in RD, likely through cone starvation due to the downregulation of RdCVF that could be reversed by insulin. Therapeutic inhibition of inflammation and stimulation of glucose availability in cones by insulin signaling might prevent RD-associated cone death until the RD can be surgically repaired and improve visual outcome after RD. ClinicalTrials.gov NCT03318588

中文翻译：

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胰岛素抑制炎症诱导的视网膜脱离视锥细胞死亡

涉及黄斑的孔源性视网膜脱离 (RD) 是视力损害的主要原因，尽管手术成功率很高，主要是因为视锥细胞死亡。RD 导致激活的免疫细胞浸润，但尚不清楚浸润的炎症细胞是否以及如何导致视锥细胞丢失。分析来自 RD 患者和黄斑裂孔对照患者的玻璃体样本，以表征对 RD 的炎症反应。然后使用 RD 和视网膜外植体培养的小鼠模型来探索导致视锥细胞死亡的机制。玻璃体样本分析证实，RD 在人类中诱导明显的炎症反应，细胞因子和趋化因子表达增加，这与实验鼠 RD 非常相似。在这个模型中，我们证实骨髓细胞和 T 淋巴细胞导致视锥细胞丢失，因为血小板反应蛋白 1 (TSP1) 抑制它们的积累增加了视锥细胞的存活率。在 RD 中使用单核细胞/视网膜共培养物和 TSP1 处理，我们证明免疫细胞浸润下调视杆细胞衍生的视锥细胞活力因子 (RdCVF)，后者在生理上调节视锥细胞中的葡萄糖摄取。尽管炎症持续存在，胰岛素和胰岛素增敏剂罗格列酮和二甲双胍在体内部分阻止了 RD 诱导的视锥细胞丢失这可以被胰岛素逆转。通过胰岛素信号传导抑制炎症和刺激视锥细胞中的葡萄糖可用性可能会阻止 RD 相关的视锥细胞死亡，直到 RD 可以通过手术修复并改善 RD 后的视力结果。临床试验.gov NCT03318588