Sphingolipids as critical players in retinal physiology and pathology

Abstract

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) emerges 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.

Lipid metabolism dysregulation in diabetic retinopathy

“…The overall role of sphingolipid metabolism in the retina is discussed in detail by Simon et al . in this issue ( 103 ).…”

Association of Human Plasma Metabolomics with Delayed Dark Adaptation in Age-Related Macular Degeneration

“…Additionally, there were four sphingolipids that were negatively associated with AUDAC. Given the role of sphingolipids in signaling pathways, multiple studies have suggested sphingolipids have a crucial role in the progression of AMD through the mediation of proliferation, survival, migration, neovascularization, inflammation, and death in retina cells [ 54 , 55 , 56 , 57 ]. As these sphingolipids were associated with AUDAC, and not RIT, it may suggest AUDAC may be a more sensitive functional measurement than RIT in measuring AMD progression due to its ability to measure DA beyond the 20 min ceiling for RIT.…”

Complement activation, lipid metabolism, and mitochondrial injury: Converging pathways in age-related macular degeneration

“…Ceramide is a bioactive lipid that regulates a wide array of cellular processes [ 108 ]. Studies on animal models of diverse retinal diseases including retinitis pigmentosa, glaucoma, diabetic retinopathy, retinal ischemia, light-induced retinal degeneration, Stargardt disease, and AMD have identified ceramide as a mediator of pathology [ 42 , 43 , 109 , 110 ]. In these models, increased ceramide has been shown to promote injury, inflammation and death in photoreceptors, the RPE, and the retinal vasculature.…”

“…Decreasing ceramide levels either pharmacologically or by genetic deletion of ASM has been shown to prevent retinal degeneration in several of these models [ 43 , 109 , 111 ]. These studies suggest that ceramide levels need to be tightly regulated in the retina, and any disruptions to the sphingolipid rheostat can have severe consequences for retinal health and function (recently reviewed in [ 110 ]).…”