Sphingolipids as critical players in retinal physiology and pathology.
Sphingolipids as critical players in retinal physiology and pathology.
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DOI：
10.1194/jlr.tr120000972
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发表时间：
2021
影响因子：
6.5
通讯作者：
Mandal N
中科院分区：
文献类型：
--
作者：
Simon MV;Basu SK;Qaladize B;Grambergs R;Rotstein NP;Mandal N
鞘脂是一种具有生物活性的脂质，参与许多生理和病理过程的调节。在视网膜中，它们已经被确定参与许多过程，例如神经元存活和死亡、神经元和血管细胞的增殖和迁移、炎症和新血管形成。因此，鞘脂的失调在视网膜疾病的发作和进展中至关重要。本文综述了鞘脂在视网膜生理和疾病中的作用。神经酰胺（Cer）已成为视网膜病如青光眼、年龄相关性黄斑变性（AMD）和色素性视网膜炎的动物模型中神经元和视网膜色素上皮细胞的炎症和死亡的常见介质。鞘氨醇-1-磷酸（S1 P）具有相反的作用，防止光感受器和神经节细胞变性，但也促进AMD、青光眼和促纤维化疾病中的炎症、纤维化和新血管形成。Cer、S1 P和1-磷酸神经酰胺的改变也可能导致葡萄膜炎。值得注意的是，使用阻止Cer增加或调节S1 P信号传导的抑制剂，如多球菌素、地昔帕明和芬戈莫德（FTY 720），保留了神经元活力和视网膜功能。这些发现强调了鞘脂代谢网络改变与多种视网膜病变病因学的相关性，并突出了调节其代谢以设计新型治疗方法的潜力。
Sphingolipids have emerged as bioactive lipids involved in the regulation of many physiological and pathological processes. In the retina, they have been established to participate in numerous processes, such as neuronal survival and death, proliferation and migration of neuronal and vascular cells, inflammation, and neovascularization. Dysregulation of sphingolipids is therefore crucial in the onset and progression of retinal diseases. This review examines the involvement of sphingolipids in retinal physiology and diseases. Ceramide (Cer) has emerged as a common mediator of inflammation and death of neuronal and retinal pigment epithelium cells in animal models of retinopathies such as glaucoma, age-related macular degeneration (AMD), and retinitis pigmentosa. Sphingosine-1-phosphate (S1P) has opposite roles, preventing photoreceptor and ganglion cell degeneration but also promoting inflammation, fibrosis, and neovascularization in AMD, glaucoma, and pro-fibrotic disorders. Alterations in Cer, S1P, and ceramide 1-phosphate may also contribute to uveitis. Notably, use of inhibitors that either prevent Cer increase or modulate S1P signaling, such as Myriocin, desipramine, and Fingolimod (FTY720), preserves neuronal viability and retinal function. These findings underscore the relevance of alterations in the sphingolipid metabolic network in the etiology of multiple retinopathies and highlight the potential of modulating their metabolism for the design of novel therapeutic approaches.