In:
Nature Communications, Springer Science and Business Media LLC, Vol. 6, No. 1 ( 2015-04-02)
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 (S1P 3 ) and Gα q , PLCβ and Ca 2+ . Intra-arterial S1P administration increases leukocyte rolling, while S1P 3 deficiency or inhibition dramatically reduces it. Mast cells involved in triggering rolling also release S1P that mobilizes P-selectin through S1P 3 . Histamine and epinephrine require S1P 3 for full-scale effect accomplishing it by stimulating sphingosine kinase 1 (Sphk1). In a counter-regulatory manner, S1P 1 inhibits cAMP-stimulated Sphk1 and blocks rolling as observed in endothelial-specific S1P 1 −/− mice. In agreement with a dominant pro-rolling effect of S1P 3 , FTY720 inhibits rolling in control and S1P 1 −/− but not in S1P 3 −/− mice. Our findings identify S1P as a direct and indirect contributor to leukocyte rolling and characterize the receptors mediating its action.
Type of Medium:
Online Resource
ISSN:
2041-1723
Language:
English
Publisher:
Springer Science and Business Media LLC
Publication Date:
2015
detail.hit.zdb_id:
2553671-0