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 () and Bodo Levkau ()
Additional contact information
Claudia Nussbaum: Walter Brendel Center, Ludwig Maximilians Universität München
Sarah Bannenberg: Institute of Pathophysiology, West German Heart and Vascular Center, University Hospital Essen, University of Duisburg-Essen
Petra Keul: Institute of Pathophysiology, West German Heart and Vascular Center, University Hospital Essen, University of Duisburg-Essen
Markus H. Gräler: Center for Sepsis Control and Care, Center for Molecular Biomedicine, University Hospital Jena
Cassiano F. Gonçalves- de-Albuquerque: Walter Brendel Center, Ludwig Maximilians Universität München
Hanna Korhonen: Max Planck Institute for Heart and Lung Research
Karin von Wnuck Lipinski: Institute of Pathophysiology, West German Heart and Vascular Center, University Hospital Essen, University of Duisburg-Essen
Gerd Heusch: Institute of Pathophysiology, West German Heart and Vascular Center, University Hospital Essen, University of Duisburg-Essen
Hugo C. de Castro Faria Neto: Laboratorio de Imunofarmacologia, Instituto Oswaldo Cruz
Ina Rohwedder: Walter Brendel Center, Ludwig Maximilians Universität München
Joachim R. Göthert: University Hospital Essen, University of Duisburg-Essen
Vysakh Pushpa Prasad: Organisch-Chemisches Institut, Westfälische Wilhelms-Universität Münster
Günter Haufe: Organisch-Chemisches Institut, Westfälische Wilhelms-Universität Münster
Baerbel Lange-Sperandio: Dr v. Haunersches Children’s Hospital, Ludwig Maximilians University München
Stefan Offermanns: Max Planck Institute for Heart and Lung Research
Markus Sperandio: Walter Brendel Center, Ludwig Maximilians Universität München
Bodo Levkau: Institute of Pathophysiology, West German Heart and Vascular Center, University Hospital Essen, University of Duisburg-Essen

Nature Communications, 2015, vol. 6, issue 1, 1-12

Abstract: 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 Ca2+. 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.

Date: 2015
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DOI: 10.1038/ncomms7416

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