Essential roles of sphingosine-1–phosphate receptor 2 in human mast cell activation, anaphylaxis, and pulmonary edema

Abstract

Systemic exacerbation of allergic responses, in which mast cells play a critical role, results in life-threatening anaphylactic shock. Sphingosine-1–phosphate (S1P), a ligand for a family of G protein–coupled receptors, is a new addition to the repertoire of bioactive lipids secreted by activated mast cells. Yet little is known of its role in human mast cell functions and in anaphylaxis. We show that S1P2 receptors play a critical role in regulating human mast cell functions, including degranulation and cytokine and chemokine release. Immunoglobulin E–triggered anaphylactic responses, including elevation of circulating histamine and associated pulmonary edema in mice, were significantly attenuated by the S1P2 antagonist JTE-013 and in S1P2-deficient mice, in contrast to anaphylaxis induced by administration of histamine or platelet-activating factor. Hence, S1P and S1P2 on mast cells are determinants of systemic anaphylaxis and associated pulmonary edema and might be beneficial targets for anaphylaxis attenuation and prophylaxis.

Mediators Released During Human Anaphylaxis

“…More recently, murine models have identified several novel mediators that may propagate and/or regulate the immune response. These include sphingosine-1-phosphate, galectin-9, IL-33, and nitric oxide [23,[33][34][35][36][37].…”

Immune Regulation by Sphingosine 1-Phosphate and Its Receptors

“…Modulation of vascular integrity was dependent on S1P 1 receptor signalling most likely in vascular endothelial cells. Investigations regarding the role of S1P during anaphylactic shock revealed an important function of the S1P 2 receptor particularly on mast cells, but presumably also on vascular endothelial cells mediating different effects at early and late stages of immunoglobulin E induced passive systemic anaphylaxis (PSA) (Olivera et al 2007(Olivera et al , 2010Oskeritzian et al 2010). S1P enhances PSA probably via activation of S1P 2 on mast cells (Olivera et al 2007;Oskeritzian et al 2010), but it also supports the recovery from PSA after its induction (Olivera et al 2010).…”

“…Investigations regarding the role of S1P during anaphylactic shock revealed an important function of the S1P 2 receptor particularly on mast cells, but presumably also on vascular endothelial cells mediating different effects at early and late stages of immunoglobulin E induced passive systemic anaphylaxis (PSA) (Olivera et al 2007(Olivera et al , 2010Oskeritzian et al 2010). S1P enhances PSA probably via activation of S1P 2 on mast cells (Olivera et al 2007;Oskeritzian et al 2010), but it also supports the recovery from PSA after its induction (Olivera et al 2010). Notably SphK1 deficient mice have lower and SphK2 deficient mice higher S1P levels in plasma than wild-type control mice (Allende et al 2004;Sensken et al 2010), and the amount of histamine measured in plasma directly after PSA induction paralleled plasma S1P levels in these mice (Olivera et al 2010).…”

“…This suggests that plasma S1P levels influence the severity of the anaphylactic shock. A possible explanation could be that the S1P 2 receptor of tissue residing mast cells is activated by S1P during early extravasation of plasma (Oskeritzian et al 2010). At later stages high plasma S1P levels help to recover from the anaphylactic shock by counteracting hypotension and promoting the elimination of histamine from plasma.…”

“…Migration to and positioning within spleen and lymph nodes of DCs in response to S1P is mediated predominantly by S1P 1 , while S1P 3 signalling can contribute to S1P 1 mediated chemotaxis depending on the developmental stage and origin of DCs (König et al 2010;Rathinasamy et al 2010). Mast cells migrate in response to S1P via stimulation of the S1P 1 receptor, but degranulation is mediated by S1P 2 activation (Oskeritzian et al 2010). Some other cells of the innate immune system use different S1P receptors for migration.…”