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Nat Commun. 2015 Apr 2;6:6416. doi: 10.1038/ncomms7416.

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

Author information

1
1] Walter Brendel Center, Ludwig Maximilians Universität München, 81377 München, Germany [2] Dr v. Haunersches Children's Hospital, Ludwig Maximilians University München, 80337 München, Germany.
2
Institute of Pathophysiology, West German Heart and Vascular Center, University Hospital Essen, University of Duisburg-Essen, 45122 Essen, Germany.
3
Department of Anesthesiology and Intensive Care Medicine, Center for Sepsis Control and Care, Center for Molecular Biomedicine, University Hospital Jena, 07745 Jena, Germany.
4
1] Walter Brendel Center, Ludwig Maximilians Universität München, 81377 München, Germany [2] Laboratorio de Imunofarmacologia, Instituto Oswaldo Cruz, Fiocruz, Rio de Janeiro 21040900, Brazil.
5
Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany.
6
Laboratorio de Imunofarmacologia, Instituto Oswaldo Cruz, Fiocruz, Rio de Janeiro 21040900, Brazil.
7
Walter Brendel Center, Ludwig Maximilians Universität München, 81377 München, Germany.
8
Department of Hematology, University Hospital Essen, University of Duisburg-Essen, 45122 Essen, Germany.
9
Organisch-Chemisches Institut, Westfälische Wilhelms-Universität Münster, 48149 Münster, Germany.
10
Dr v. Haunersches Children's Hospital, Ludwig Maximilians University München, 80337 München, Germany.

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.

PMID:
25832730
PMCID:
PMC4396399
DOI:
10.1038/ncomms7416
[Indexed for MEDLINE]
Free PMC Article

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