Center for Cell Clearance, University of Virginia, Charlottesville, VA, USA.
Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, VA, USA.
Nat Metab. 2023 Feb;5(2):207-218. doi: 10.1038/s42255-022-00728-0. Epub 2023 Feb 2.
The retina is highly metabolically active, relying on glucose uptake and aerobic glycolysis. Situated in close contact to photoreceptors, a key function of cells in the retinal pigment epithelium (RPE) is phagocytosis of damaged photoreceptor outer segments (POS). Here we identify RPE as a local source of insulin in the eye that is stimulated by POS phagocytosis. We show that Ins2 messenger RNA and insulin protein are produced by RPE cells and that this production correlates with RPE phagocytosis of POS. Genetic deletion of phagocytic receptors ('loss of function') reduces Ins2, whereas increasing the levels of the phagocytic receptor MerTK ('gain of function') increases Ins2 production in male mice. Contrary to pancreas-derived systemic insulin, RPE-derived local insulin is stimulated during starvation, which also increases RPE phagocytosis. Global or RPE-specific Ins2 gene deletion decreases retinal glucose uptake in starved male mice, dysregulates retinal physiology, causes defects in phototransduction and exacerbates photoreceptor loss in a mouse model of retinitis pigmentosa. Collectively, these data identify RPE cells as a phagocytosis-induced local source of insulin in the retina, with the potential to influence retinal physiology and disease.
视网膜具有高度的代谢活性，依赖于葡萄糖摄取和有氧糖酵解。视网膜色素上皮 (RPE) 中的细胞与光感受器紧密接触，其主要功能之一是吞噬受损的光感受器外节 (POS)。在这里，我们确定 RPE 是眼睛中胰岛素的局部来源，其受 POS 吞噬作用的刺激。我们表明，RPE 细胞产生 Ins2 信使 RNA 和胰岛素蛋白，并且这种产生与 RPE 对 POS 的吞噬作用相关。吞噬受体的基因缺失（“功能丧失”）会降低 Ins2，而增加吞噬受体 MerTK 的水平（“功能获得”）会增加雄性小鼠中的 Ins2 产生。与胰腺产生的全身胰岛素相反，RPE 产生的局部胰岛素在饥饿时受到刺激，这也会增加 RPE 的吞噬作用。全身性或 RPE 特异性 Ins2 基因缺失会降低饥饿雄性小鼠的视网膜葡萄糖摄取，扰乱视网膜生理学，导致光转导缺陷，并在色素性视网膜炎的小鼠模型中加剧光感受器损失。总之，这些数据表明 RPE 细胞是视网膜中受吞噬作用诱导的胰岛素的局部来源，具有影响视网膜生理学和疾病的潜力。
