Sphingosine-1-phosphate receptor 3 promotes leukocyte rolling by mobilizing endothelial P-selectin.

Claudia Nussbaum, Sarah Bannenberg, Petra Keul, Markus H Gräler, Cassiano F Gonçalves-de-Albuquerque, Hanna Korhonen, Karin von Wnuck Lipinski, Gerd Heusch, Hugo C de Castro Faria Neto, Ina Rohwedder, Joachim R Göthert, Vysakh Pushpa Prasad, Günter Haufe, Baerbel Lange-Sperandio, Stefan Offermanns, Markus Sperandio, Bodo Levkau

Index: Nat. Commun. 6 , 6416, (2015)

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Abstract

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.