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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / metabolism
  • Endothelium, Vascular / metabolism*
  • Epinephrine / metabolism
  • GTP-Binding Protein alpha Subunits, Gq-G11 / metabolism
  • Histamine / metabolism
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Immunohistochemistry
  • Leukocyte Rolling / genetics*
  • Lysophospholipids / metabolism
  • Male
  • Mast Cells / metabolism
  • Mice
  • Mice, Knockout
  • Muscle, Skeletal / blood supply
  • P-Selectin / metabolism*
  • Phospholipase C beta / metabolism
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism
  • Receptors, Lysosphingolipid / genetics*
  • Receptors, Lysosphingolipid / metabolism
  • Sphingosine / analogs & derivatives
  • Sphingosine / metabolism
  • Sphingosine-1-Phosphate Receptors
  • Venules

Substances

  • Lysophospholipids
  • P-Selectin
  • Receptors, Lysosphingolipid
  • S1pr3 protein, mouse
  • Sphingosine-1-Phosphate Receptors
  • sphingosine-1-phosphate receptor-3, human
  • sphingosine 1-phosphate
  • Histamine
  • Phosphotransferases (Alcohol Group Acceptor)
  • sphingosine kinase
  • Phospholipase C beta
  • GTP-Binding Protein alpha Subunits, Gq-G11
  • Sphingosine
  • Calcium
  • Epinephrine