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.

Sphingosine-1-phosphate receptor 2 protects against anaphylactic shock through suppression of endothelial nitric oxide synthase in mice

“…These distinct signaling properties likely underlie the differential roles of S1P 1 and S1P 2 in the regulation of barrier integrity: S1pr2 deficiency does not affect baseline vascular permeability but prevents enhanced vascular leakage after antigen challenge or injections of PAF and histamine (Figs 1, and Figs E1 and E2). 20 Consistent with this is the previous observation that baseline permeability was not affected by the presence or absence of eNOS. 22,23 Different from S1P 2 , S1P 1 maintains not only constitutive barrier integrity but protects against barrier disruption caused by anaphylaxis and inflammation.…”

“…These results together imply that S1P 2 alleviates acute vascular permeability largely by acting at a site distal to the release of anaphylactic mediators from mast cells; i.e., very likely at the vasculature itself. Our observations are consistent with the studies by Olivera et al, 20,21 which showed that histamine injection-induced hypothermia and hypotension were aggravated in S1pr2 -/-mice, but are not consistent with that by Oskeritzian et al, 19 which showed that S1pr2 deficiency alleviated vascular leakage and hypothermia after antigen challenge, contrasting to our study. The findings by Oskeritzian et al 19 also differ from our observations, in that PAF or histamine injection-induced vascular leakage and hypothermia were not different between Cui 18 S1pr2 -/-and WT mice.…”

“…Unlike this report, however, another group showed that S1P 2 was rather vital for recovery from histamine-induced hypothermia through regulating vascular tone and histamine clearance, which suggests that S1P 2 exerts a protective effect against anaphylaxis at a site distal to mast cell activation. 20,21 Thus, the in vivo role of S1P 2 in anaphylaxis is not yet fully understood.…”

Proximal Cerebral Arteries Develop Myogenic Responsiveness in Heart Failure via Tumor Necrosis Factor-α–Dependent Activation of Sphingosine-1-Phosphate Signaling

“…Although MAP levels appeared to be lower than in the other tested cohorts, these observations are unlikely to be attributable to the Sphk1 Ϫ/Ϫ genotype. 28 Because autoregulation serves to maintain organ blood flow during fluctuations in perfusion pressure, the observed lack of correlation between CBF and MAP in Sphk1 Ϫ/Ϫ sham and HF mice indicates that autoregulatory mechanisms were functioning under both conditions (Figure 7). Despite intact autoregulation, CBF measures were qualitatively lower than in the other cohorts, suggesting the presence of a specific Sphk1 Ϫ/Ϫ phenotype.…”

Isoflurane activates intestinal sphingosine kinase to protect against bilateral nephrectomy-induced liver and intestine dysfunction

“…SK1 mediates ischemic postconditioning in mouse hearts (23) and protects against lipopolysaccharide-induced lung injury via downregulation of JNK (8). Mice deficient in the SK1 enzyme had poor recovery from anaphylaxis and delayed histamine clearance, while mice deficient in the SK2 enzyme had rapid recovery from anaphylaxis (44). In contrast, certain models of inflammation such as Crohn's disease show a deleterious effect of SK as mice treated with an SK inhibitor (39) or mice deficient in the SK1 enzyme (51) had reduced inflammation and colon damage.…”