Sphingosine-1-Phosphate Is a Crucial Signal for Migration of Retina Müller Glial Cells.
| Autor: | Simón MV, Prado Spalm FH, Politi LE, Rotstein NP |
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| Jazyk: | angličtina |
| Zdroj: | Investigative ophthalmology & visual science [Invest Ophthalmol Vis Sci] 2015 Sep; Vol. 56 (10), pp. 5808-15. |
| DOI: | 10.1167/iovs.14-16195 |
| Abstrakt: | Purpose: Migration of Müller glial cells is enhanced in proliferative retinopathies, but the mechanisms involved are ill defined. Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid synthesized by sphingosine kinase (SphK), which promotes proliferation, migration, and inflammation, acting as an intracellular mediator and activating a family of membrane receptors (S1PRs). We investigated whether S1P regulated glial migration. Methods: Müller glial cell cultures from rat retinas were supplemented with 5 μM S1P, and migration was evaluated by scratch-wound assays. Cultures were treated with SphK inhibitor 2 (SphKI 2), a SphK1 inhibitor, or with W146 and BML-241, S1P1 and S1P3 antagonists, respectively, to investigate whether Müller glial cells synthesized S1P and S1P-activated S1PRs to stimulate migration. The effects of LY294002, U0126, and SB203580, which are phosphatidylinositol-3 kinase (PI3K), extracellular signal regulated kinase/mitogen-activated protein kinase (ERK/MAPK), and p38 MAPK inhibitors, respectively, on glial migration were determined. Results: Sphingosine-1-phosphate addition prompted the formation of lamellipodia and enhanced glial migration. SphKI 2 almost completely prevented glial migration in controls; BML-241 inhibited this migration both in controls and in S1P-supplemented cultures, whereas W146 had no significant effect. Pretreatment with LY294002 and U0126 abrogated glial migration; SB203580 decreased it partially, although not significantly. Conclusions: Our results suggest that Müller glial cells synthesize S1P, which signals through S1P3 and the PI3K and ERK/MAPK pathways to induce glial migration. As a whole, our data point to a central role for S1P in controlling glial cell motility. Because deregulation of this process is involved in several retinal pathologies, S1P signaling emerges as a potential tool for treating these diseases. |
| Databáze: | MEDLINE |
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