Mast cells are key players in the development of inflammatory allergic reactions. Cross-linking of the high-affinity receptor for IgE (FcεRI) on mast cells leads to the generation and secretion of the sphingolipid mediator, sphingosine-1-phosphate (S1P) which is able, in turn, to transactivate its receptors on mast cells. Previous reports have identified the expression of two of the five receptors for S1P on mast cells, S1P₁ and S1P₂, with functions in FcεRI-mediated chemotaxis and degranulation, respectively. Here, we show that cultured mouse mast cells also express abundant message for S1P₄. Genetic deletion of S1pr4 did not affect the differentiation of bone marrow progenitors into mast cells or the proliferation of mast cells in culture. A comprehensive characterization of IgE-mediated responses in S1P₄-deficient bone marrow-derived and peritoneal mouse mast cells indicated that this receptor is dispensable for mast cell degranulation, cytokine/chemokine production and FcεRI-mediated chemotaxis in vitro. However, interleukin-33 (IL-33)-mediated enhancement of IgE-induced degranulation was reduced in S1P₄-deficient peritoneal mast cells, revealing a potential negative regulatory role for S1P₄ in an IL-33-rich environment. Surprisingly, genetic deletion of S1pr4 resulted in exacerbation of passive systemic anaphylaxis to IgE/anti-IgE in mice, a phenotype likely related to mast cell-extrinsic influences, such as the high circulating levels of IgE in these mice which increases FcεRI expression and consequently the extent of the response to FcεRI engagement. Thus, we provide evidence that S1P₄ modulates anaphylaxis in an unexpected manner that does not involve regulation of mast cell responsiveness to IgE stimulation.
Pubmed ID: 29693558 RIS Download
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Software for single-cell flow cytometry analysis. Its functions include management, display, manipulation, analysis and publication of the data stream produced by flow and mass cytometers.
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