Sphingosine kinase 1 and sphingosine-1-phosphate receptor 2 are vital to recovery from anaphylactic shock in mice.
Sphingosine kinase 1 (SphK1) and SphK2 are ubiquitous enzymes that generate sphingosine-1-phosphate (S1P), a ligand for a family of G protein-coupled receptors (S1PR1-S1PR5) with important functions in the vascular and immune systems. Here we explore the role of these kinases and receptors in recovery from anaphylaxis in mice. We found that Sphk2-/- mice had a rapid recovery from anaphylaxis. In contrast, Sphk1-/- mice showed poor recovery from anaphylaxis and delayed histamine clearance. Injection of S1P into Sphk1-/- mice increased histamine clearance and promoted recovery from anaphylaxis. Adoptive cell transfer experiments demonstrated that SphK1 activity was required in both the hematopoietic and nonhematopoietic compartments for recovery from anaphylaxis. Mice lacking the S1P receptor S1PR2 also showed a delay in plasma histamine clearance and a poor recovery from anaphylaxis. However, S1P did not promote the recovery of S1pr2-/- mice from anaphylaxis, whereas S1pr2+/- mice showed partial recovery. Unlike Sphk2-/- mice, Sphk1-/- and S1pr2-/- mice had severe hypotension during anaphylaxis. Thus, SphK1-produced S1P regulates blood pressure, histamine clearance, and recovery from anaphylaxis in a manner that involves S1PR2. This suggests that specific S1PR2 agonists may serve to counteract the vasodilation associated with anaphylactic shock.
Olivera
Ana
A
Laboratory of Molecular Immunogenetics, National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, Maryland 20892, USA.
Eisner
Christoph
C
Kitamura
Yoshiaki
Y
Dillahunt
Sandra
S
Allende
Laura
L
Tuymetova
Galina
G
Watford
Wendy
W
Meylan
Francoise
F
Diesner
Susanne C
SC
Li
Lingli
L
Schnermann
Jurgen
J
Proia
Richard L
RL
Rivera
Juan
J
D000707:Anaphylaxis / Q000201:enzymology*; D000818:Animals; D016026:Bone Marrow Transplantation; D015971:Gene Expression Regulation, Enzymologic; D005919:Glomerular Filtration Rate; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006632:Histamine / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D010539:Permeability; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism*; D049349:Receptors, Lysosphingolipid / Q000378:metabolism*; D000099157:Sphingosine Kinase
D006632:Histamine; D017853:Phosphotransferases (Alcohol Group Acceptor); D049349:Receptors, Lysosphingolipid; D000099157:Sphingosine Kinase
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