Transactivation of Sphingosine-1–Phosphate Receptors by FcεRI Triggering Is Required for Normal Mast Cell Degranulation and Chemotaxis

Mast cells secrete various substances that initiate and perpetuate allergic responses. Cross-linking of the high-affinity receptor for IgE (FcεRI) in RBL-2H3 and bone marrow–derived mast cells activates sphingosine kinase (SphK), which leads to generation and secretion of the potent sphingolipid mediator, sphingosine-1–phosphate (S1P). In turn, S1P activates its receptors S1P₁ and S1P₂ that are present in mast cells. Moreover, inhibition of SphK blocks FcεRI-mediated internalization of these receptors and markedly reduces degranulation and chemotaxis. Although transactivation of S1P₁ and Gi signaling are important for cytoskeletal rearrangements and migration of mast cells toward antigen, they are dispensable for FcεRI-triggered degranulation. However, S1P₂, whose expression is up-regulated by FcεRI cross-linking, was required for degranulation and inhibited migration toward antigen. Together, our results suggest that activation of SphKs and consequently S1PRs by FcεRI triggering plays a crucial role in mast cell functions and might be involved in the movement of mast cells to sites of inflammation.