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Nussbaum, Claudia; Bannenberg, Sarah; Keul, Petra; Gräler, Markus H.; Goncalves-de-Albuquerque, Cassiano F.; Korhonen, Hanna; Lipinski, Karin von Wnuck; Heusch, Gerd; Castro Faria Neto, Hugo C. de; Rohwedder, Ina; Göthert, Joachim R.; Prasad, Vysakh Pushpa; Haufe, Günter; Lange-Sperandio, Baerbel; Offermanns, Stefan; Sperandio, Markus and Levkau, Bodo (2015): Sphingosine-1-phosphate receptor 3 promotes leukocyte rolling by mobilizing endothelial P-selectin. In: Nature Communications, Vol. 6, 6416 [PDF, 1MB]

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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 (S1P(3)) and G alpha(q), PLC beta and Ca2+. Intraarterial S1P administration increases leukocyte rolling, while S1P(3) deficiency or inhibition dramatically reduces it. Mast cells involved in triggering rolling also release S1P that mobilizes P-selectin through S1P(3). Histamine and epinephrine require S1P(3) 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 S1P(1)(-/-) mice. In agreement with a dominant pro-rolling effect of S1P(3),FTY720 inhibits rolling in control and S1P(1)(-/-) but not in S1P(3)(-/-) mice. Our findings identify S1P as a direct and indirect contributor to leukocyte rolling and characterize the receptors mediating its action.

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