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 recove...

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Veröffentlicht in:The Journal of clinical investigation 2010-05, Vol.120 (5), p.1429-1440
Hauptverfasser: Olivera, A, Eisner, C, Kitamura, Y, Dillahunt, S, Allende, L, Tuymetova, G, Watford, W, Meylan, F, Diesner, S C, Li, L, Schnermann, J, Praia, RL, Rivera, J
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Sprache:eng
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Zusammenfassung: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 ana-phylaxis in mice. We found that Spbk2 super(-/-) mice had a rapid recovery from anaphylaxis. In contrast, Spbk1 super(-/-) mice showed poor recovery from anaphylaxis and delayed histamine clearance. Injection of S1Pinto Spbk1 super(-/-) 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 SIP receptor S1PR2 also showed a delay in plasma histamine clearance and a poor recovery from anaphylaxis. However, S1P did not promote the recovery of S1br2 super(-/-) mice from anaphylaxis, whereas Spbk2 super(+/-) mice showed partial recovery. Unlike Spbk2 super(-/-) mice, Spbk1 super(-/-) and S1pr2 super(-/-) 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.
ISSN:0021-9738
DOI:10.1172/JCI406S9