Article
Sphingosine-1-phosphate receptor 3 promotes leukocyte rolling by mobilizing endothelial P-selectin
Registro en:
NUSSBAUM, Claudia; et al. Sphingosine-1-phosphate receptor 3 promotes leukocyte rolling by mobilizing endothelial P-selectin. Nature Communications, 6:6416, 12p, 2015.
2041-1723
10.1038/ncomms7416
Autor
Nussbaum, Claudia
Bannenberg, Sarah
Keul, Petra
Gräler, Markus H.
Albuquerque, Cassiano F. Gonçalves de
Korhonen, Hanna
Lipinski, Karin von Wnuck
Heusch, Gerd
Faria Neto, Hugo C. de Castro
Rohwedder, Ina
Göther, Joachim R.
Prasad, Vysakh Pushpa
Haufe, Günter
Lange-Sperandio, Baerbel
Offermanns, Stefan
Sperandio, Markus
Levkau, Bodo
Resumen
Sphingosine-1-phosphate (S1P) participates in inflammation; however, its role in leukocyte rolling is still unclear. Here we use intravital microscopy in inflamed mouse cremaster muscle venules and human endothelial cells to show that S1P contributes to P-selectin-dependent leukocyte rolling through endothelial S1P receptor 3 (S1P3) and Gαq, PLCβ and Ca(2+). Intra-arterial S1P administration increases leukocyte rolling, while S1P3 deficiency or inhibition dramatically reduces it. Mast cells involved in triggering rolling also release S1P that mobilizes P-selectin through S1P3. Histamine and epinephrine require S1P3 for full-scale effect accomplishing it by stimulating sphingosine kinase 1 (Sphk1). In a counter-regulatory manner, S1P1 inhibits cAMP-stimulated Sphk1 and blocks rolling as observed in endothelial-specific S1P1(-/-) mice. In agreement with a dominant pro-rolling effect of S1P3, FTY720 inhibits rolling in control and S1P1(-/-) but not in S1P3(-/-) mice. Our findings identify S1P as a direct and indirect contributor to leukocyte rolling and characterize the receptors mediating its action.