Sphingosine kinase 1 and sphingosine-1-phosphate receptor 2 are vital to recovery from anaphylactic shock in mice
Ana Olivera, Christoph Eisner, Yoshiaki Kitamura, Sandra Dillahunt, Laura Allende, Galina Tuymetova, Wendy Watford, Francoise Meylan, Susanne C. Diesner, Lingli Li, Jurgen Schnermann, Richard L. Proia, Juan Rivera
Ana Olivera, Christoph Eisner, Yoshiaki Kitamura, Sandra Dillahunt, Laura Allende, Galina Tuymetova, Wendy Watford, Francoise Meylan, Susanne C. Diesner, Lingli Li, Jurgen Schnermann, Richard L. Proia, Juan Rivera
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Research Article Immunology

Sphingosine kinase 1 and sphingosine-1-phosphate receptor 2 are vital to recovery from anaphylactic shock in mice

Abstract

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.

Authors

Ana Olivera, Christoph Eisner, Yoshiaki Kitamura, Sandra Dillahunt, Laura Allende, Galina Tuymetova, Wendy Watford, Francoise Meylan, Susanne C. Diesner, Lingli Li, Jurgen Schnermann, Richard L. Proia, Juan Rivera

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Figure 7

Loss of blood pressure is more pronounced in Sphk1–/– and S1pr2–/– mice when compared with WT mice but is less severe in Sphk2–/– mice.

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Loss of blood pressure is more pronounced in Sphk1–/– and S1pr2–/– mice ...
(A) MAP before (10 minutes) and after (30 minutes) histamine injection (5 μmol; at time 0) in isoflurane-anesthetized WT (n = 9), Sphk1–/– (n = 6), and Sphk2–/– mice (n = 6). Graph lines connect mean values of MAP at 2-minute intervals. *P < 0.05, between WT and Sphk–/– mice, determined by Student’s t test. (B) MAP of anesthetized Sphk1–/– mice after histamine injection alone or in combination with S1P treatment (10 minutes after histamine bolus as indicated). The effect of S1P on MAP in the WT mice under anaphylaxis was about half of that seen in the Sphk1–/– mice (data not shown). (C and D) Blood flow in conscious mice determined by pulse distension measurements in (D) WT (n = 6), Sphk1–/– (n = 6), and Sphk2–/– (n = 6) mice or (C) S1pr2–/– (n = 6) and their WT (S1pr2+/+) counterparts (n = 4) at baseline and at 30, 60, and 120 minutes after histamine bolus. *P < 0.05, **P < 0.01, ***P < 0.001, compared with baseline, determined by a Student’s t test.