title: Sphingosine-1-phosphate receptor 3 promotes leukocyte rolling by mobilizing endothelial P-selectin.
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.
authors.affiliation: 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.
authors.forename: Claudia
authors.initials: C
authors.lastname: Nussbaum
authors.affiliation: Institute of Pathophysiology, West German Heart and Vascular Center, University Hospital Essen, University of Duisburg-Essen, 45122 Essen, Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Bannenberg
authors.affiliation: Institute of Pathophysiology, West German Heart and Vascular Center, University Hospital Essen, University of Duisburg-Essen, 45122 Essen, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Keul
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Center for Sepsis Control and Care, Center for Molecular Biomedicine, University Hospital Jena, 07745 Jena, Germany.
authors.forename: Markus H
authors.initials: MH
authors.lastname: Gräler
authors.affiliation: 1] Walter Brendel Center, Ludwig Maximilians Universität München, 81377 München, Germany [2] Laboratorio de Imunofarmacologia, Instituto Oswaldo Cruz, Fiocruz, Rio de Janeiro 21040900, Brazil.
authors.forename: Cassiano F
authors.initials: CF
authors.lastname: Gonçalves-de-Albuquerque
authors.affiliation: Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany.
authors.forename: Hanna
authors.initials: H
authors.lastname: Korhonen
authors.affiliation: Institute of Pathophysiology, West German Heart and Vascular Center, University Hospital Essen, University of Duisburg-Essen, 45122 Essen, Germany.
authors.forename: Karin
authors.initials: K
authors.lastname: von Wnuck Lipinski
authors.affiliation: Institute of Pathophysiology, West German Heart and Vascular Center, University Hospital Essen, University of Duisburg-Essen, 45122 Essen, Germany.
authors.forename: Gerd
authors.initials: G
authors.lastname: Heusch
authors.affiliation: Laboratorio de Imunofarmacologia, Instituto Oswaldo Cruz, Fiocruz, Rio de Janeiro 21040900, Brazil.
authors.forename: Hugo C
authors.initials: HC
authors.lastname: de Castro Faria Neto
authors.affiliation: Walter Brendel Center, Ludwig Maximilians Universität München, 81377 München, Germany.
authors.forename: Ina
authors.initials: I
authors.lastname: Rohwedder
authors.affiliation: Department of Hematology, University Hospital Essen, University of Duisburg-Essen, 45122 Essen, Germany.
authors.forename: Joachim R
authors.initials: JR
authors.lastname: Göthert
authors.affiliation: Organisch-Chemisches Institut, Westfälische Wilhelms-Universität Münster, 48149 Münster, Germany.
authors.forename: Vysakh Pushpa
authors.initials: VP
authors.lastname: Prasad
authors.affiliation: Organisch-Chemisches Institut, Westfälische Wilhelms-Universität Münster, 48149 Münster, Germany.
authors.forename: Günter
authors.initials: G
authors.lastname: Haufe
authors.affiliation: Dr v. Haunersches Children's Hospital, Ludwig Maximilians University München, 80337 München, Germany.
authors.forename: Baerbel
authors.initials: B
authors.lastname: Lange-Sperandio
authors.affiliation: Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Offermanns
authors.affiliation: Walter Brendel Center, Ludwig Maximilians Universität München, 81377 München, Germany.
authors.forename: Markus
authors.identifier: 0000000276893613
authors.initials: M
authors.lastname: Sperandio
authors.affiliation: Institute of Pathophysiology, West German Heart and Vascular Center, University Hospital Essen, University of Duisburg-Essen, 45122 Essen, Germany.
authors.forename: Bodo
authors.initials: B
authors.lastname: Levkau
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism*; D004837:Epinephrine / Q000378:metabolism; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000378:metabolism; D006632:Histamine / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007150:Immunohistochemistry; D036904:Leukocyte Rolling / Q000235:genetics*; D008246:Lysophospholipids / Q000378:metabolism; D008297:Male; D008407:Mast Cells / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000098:blood supply; D019007:P-Selectin / Q000378:metabolism*; D054799:Phospholipase C beta / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D049349:Receptors, Lysosphingolipid / Q000235:genetics* / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism; D000081025:Sphingosine-1-Phosphate Receptors; D014699:Venules; D000099157:Sphingosine Kinase
chemical_list: D002118:Calcium; D004837:Epinephrine; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D006632:Histamine; D008246:Lysophospholipids; D019007:P-Selectin; D054799:Phospholipase C beta; D017853:Phosphotransferases (Alcohol Group Acceptor); D049349:Receptors, Lysosphingolipid; D013110:Sphingosine; D000081025:Sphingosine-1-Phosphate Receptors; D000099157:Sphingosine Kinase; C501285:S1pr3 protein, mouse; C577483:sphingosine-1-phosphate receptor-3, human; C060506:sphingosine 1-phosphate
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