Multiple roles of sphingosine-1-phosphate in neuro-glia crosstalk in the retina.

PRADO SPALM F.H.; SIMON M.V.; VERA M; POLITI L.E.; ROTSTEIN N.P.

Puerto Iguazú, Misiones

Congreso; 56th International Conference on the Bioscience of Lipids (ICBL); 2015

ICBL

SPHINGOSINE-1-PHOSPHATE IS INVOLVED IN GLIAL PROTECTION OF RETINA PHOTORECEPTORSPrado Spalm FH, Simón MV, Vera M, Politi LE, Rotstein NP.Institute of Biochemical Research, Universidad Nacional del Sur-CONICET, Bahia Blanca, Argentina. Email: fpradospalm@inibibb-conicet.gob.arDeath of photoreceptors is a leitmotif of retinal degenerations and identifying mediators that promote their survival might provide new therapeutical targets. Sphingosine-1-phosphate (S1P) is a potent sphingolipid mediator that regulates proliferation, survival, migration and inflammation. S1P is synthesized by sphingosine kinase 1 (SphK1) and acts as an intracellular messenger or is released to activate a family of S1P membrane receptors (S1PRs). S1P roles in the retina are still poorly understood. We demonstrated that S1P promotes proliferation and differentiation in photoreceptors and rescues them from oxidative stress-induced apoptosis. Here we explored the molecular pathways involved in S1P effects and whether it participates in neuro-glia crosstalk. S1P addition to pure neuronal cultures from rat retinas rapidly increased P-ERK levels in photoreceptors compared to controls. Pretreatment of these cultures with an inhibitor of the ERK/MAPK pathway abrogated S1P protection of photoreceptors from H2O2-induced oxidative stress. RT-PCR evidenced the expression of S1P2 and S1P3 in neurons, whereas the presence of S1P3 in photoreceptors was determined by immunocytochemistry. Treatment of these cultures with a S1P3 antagonist blocked S1P protection from oxidative damage. Since Muller glial cells protect photoreceptors in co-culture from oxidative stress, we evaluated whether S1P might be among the signals released by glial cells to promote this protection. Inhibiting SphK1 decreased glial protection of photoreceptors from oxidative stress-induced apoptosis. These results suggest that S1P activates the S1P3 and subsequently the ERK/MAPK pathway to promote photoreceptor survival. They also imply that glial cells synthesize and release S1P to exert its protective effects on photoreceptors.