Sphingosine-1-phosphate signaling in retina photoreceptors and glial cells

Abstract

Sphingosine-1-phosphate (S1P) is a potent sphingolipid mediator that regulates proliferation, survival, migration and inflammation in different cell types, acting on S1P membrane receptors (S1PRs) or as an intracellular messenger. S1P roles in the retina are still poorly understood. We have demonstrated that S1P promotes proliferation and differentiation in photoreceptors and rescues them from oxidative stress–induced apoptosis. We here investigated the pathways leading to S1P protective effect. Pretreatment of neuronal cultures with a S1PR antagonist or with PD98059, an ERK/MAPK pathway inhibitor, abolished S1P protection from oxidative stress, while LY294002, a PI3 kinase inhibitor, had no effect. This implies S1P activates S1PRs in photoreceptors, which then promote photoreceptor survival through the ERK/MAPK pathway. Since we have shown that Müller glial cells protect photoreceptors from oxidative stress–induced apoptosis, we explored whether S1P was involved in this protection. In neuro-glial cultures grown in S1P-lacking media, addition of an inhibitor of S1P synthesis or an S1PR antagonist blocked glial protection, suggesting glial cells synthesize and release S1P to promote photoreceptor survival. We also studied whether S1P regulated proliferation and migration of Müller glial cells, known to be involved in proliferative retinopathies. S1P enhanced glial proliferation and inhibiting the PI3K pathway blocked this effect. S1P also induced glial cell migration; S1P addition prompted formation of lamellipodia in glial cells, which then rapidly migrated in a scratch-wound assay. A S1PR antagonist or LY294002 blocked this migration, while PD98059 and SB203580, a p38 MAPK inhibitor, partially prevented it. Hence, S1P promotes glial proliferation and migration through activation of different intracellular pathways. As a whole, our data point to a central role for S1P in the control of crucial processes in both photoreceptors and glial cells. Since deregulation of these processes is involved in several retinal pathologies, S1P signaling emerges as a potential tool for treating these diseases.