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) 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.

Keywords: age-related macular degeneration; ceramide; ceramide-1-phosphate; photoreceptor degeneration; retinitis pigmentosa; sphingosine-1-phosphate.

Fig. 1

Chemical structures of sphingolipids. The Sph backbone (black) is shared by all sphingolipids. Sph is amide-linked to a fatty acid moiety (brown), forming Cer. Later additions of a phosphate (blue) or hexose residues (orange) give rise to several sphingolipid molecules.

Fig. 2

The sphingolipid networks. A schematic view of the interconnected sphingolipid network, which has Cers (purple) forming its central hub. Cer can be synthesized through the de novo pathway (green), initiated by the condensation of l-serine and palmitoyl-CoA; through the SMase pathway (blue), from the degradation of SM catalyzed by different SMases; or through the Salvage pathway (yellow), from the Sph generated by the degradation of complex sphingolipids. Cer can then serve as a substrate for sphingomyelin synthesis by SMS; be phosphorylated by a CerK to generate C1P; or be deacylated by CDases to form Sph, which can in turn be phosphorylated by SphK to produce S1P. S1P can be dephosphorylated by S1P phosphatase (S1PP) to regenerate Sph or be irreversibly degraded by S1P lyase to render ethanolamine 1-phosphate and hexadecenal, an irreversible reaction that provides the only escape pathway from this intricate metabolic network. DES, dihydroceramide desaturase-1; LPP, lipid phosphate phosphatases.