Sphingosine kinase 1 and sphingosine-1-phosphate receptor 2 are vital to recovery from anaphylactic shock in mice
Ana Olivera, … , Richard L. Proia, Juan Rivera
Ana Olivera, … , Richard L. Proia, Juan Rivera
Published April 19, 2010
Citation Information: J Clin Invest. 2010;120(5):1429-1440. https://doi.org/10.1172/JCI40659.
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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 2

Involvement of SphK1, in the hematopoietic and nonhematopoietic compartment, in the intensity and recovery from anaphylaxis.

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Involvement of SphK1, in the hematopoietic and nonhematopoietic compartm...
Bone marrow cells from WT or Sphk1–/– mice were adoptively transferred into lethally irradiated WT or Sphk1–/– recipient mice. After engraftment of donor bone marrow cells, mice were subjected to histamine-induced anaphylaxis. (A) A representative figure of PCR-based genotyping results from DNA extracted from tail samples (a) or whole blood (b) of recipient mice showing appropriate engraftment. WT mice showed a 300-bp fragment, whereas Sphk1–/– mice showed a 350-bp fragment. (B) Plasma S1P levels of mice in A were measured as previously described (15). ***P < 0.001, determined by Student’s t test. (C) Body temperature measurements of the lethally irradiated, bone marrow–transplanted mice after a histamine bolus. WT-BMT(WT) mice are lethally irradiated WT recipients reconstituted with donor WT bone marrow cells (n = 13); WT-BMT(Sphk1–/–) mice are WT recipients reconstituted with donor Sphk1–/– bone marrow cells (n = 8); Sphk1–/–-BMT(WT) mice are Sphk1–/– recipients reconstituted with donor WT bone marrow cells (n = 12); and Sphk1–/–-BMT(Sphk1–/–) mice are Sphk1–/– recipients reconstituted with donor Sphk1–/– bone marrow cells (n = 6). **P < 0.01, ***P < 0.001, determined using 2-way ANOVA. Blood analysis in all the lethally-irradiated, bone marrow–transplanted mice showed cell counts similar to those of WT mice, indicating successful engrafting. The blood cell counts present in all chimeras were as follows: lymphocytes, ≥4 × 106/ml; rbc, ~10–11 × 106/μl, platelets, ~2.4–3.8 × 107/ml; monocytes, ~0.5–1.3 × 106/ml; and polymorphonucleated cells, ~1.5–2.6 × 106/ml.