Sphingosine-1-phosphate is a key mediator of glial cell migration in the retina

SIMON M.V.; PRADO SPALM F.H.; 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 A KEY MEDIATOR OF GLIAL CELL MIGRATION IN THE RETINA Simón MV, Prado Spalm FH, Vera M, Politi LE, Rotstein NP.Institute of Biochemical Research, Universidad Nacional del Sur-CONICET, Bahia Blanca, Argentina. Email: inrotste@criba.edu.arMigration of Müller glial cells is enhanced in proliferative retinopathies that lead to visual dysfunction, and signals involved in this migration are ill defined. Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid synthesized by sphingosine kinase (SphK1), which promotes proliferation, migration and inflammation. S1P acts as an intracellular mediator or is released to activate a family of membrane receptors (S1PRs), by ?inside-out signaling?. We here investigated whether S1P promotes glial migration. Müller glial cell cultures prepared from rat retinas were supplemented with 5 µM S1P and migration was evaluated by scratch-wound assays. S1P addition enhanced glial migration. Glial cells expressed S1P1, S1P2 and S1P3. Treatment of glial cultures with BML-241, a S1P3 antagonist, inhibited their migration both in controls and in S1P-supplemented cultures, whereas a S1P1 antagonist had no effect. Addition of a SphK1 inhibitor abrogated glial migration, suggesting glial cells synthesized S1P to promote their migration. Pretreatment with LY294002 and U0126, PI3K and ERK/MAPK inhibitors, blocked S1P-induced glial migration whereas SB203580, a p38 MAPK inhibitor, partially, though not significantly, reduced it. Pretreatment with TIMP-1, a pan-metalloproteinase inhibitor, significantly reduced S1P-induced migration.Our results suggest that glial cells synthesize and release S1P, which then signals through S1P3 and the PI3K and ERK/MAPK pathways, activating metalloproteinases to induce glial migration. As a whole, they point to a central role for the S1P/S1P3 axis in controlling glial cell motility. Since deregulation of this process is involved in several retinal pathologies, S1P signaling emerges as a potential tool for treating these devastating diseases.