IgE-dependent anaphylaxis is regulated by sphingolipid binding to activating and inhibitory CD300 family members

Immunoglobulin E (IgE)-dependent mast cell degranulation and anaphylaxis are suppressed by the CD300f-ceramide interaction. However, the related, positive regulatory mechanisms remain unclear. Here, we examine the effect of FcεRIγ-coupled CD300d3 on IgE-dependent anaphylaxis in mice. We identify sphingomyelin (SM) species as CD300d3 ligands, of which certain types bind CD300f. Stimulation with SM recognized by CD300d3, but not strongly by CD300f (referred to here as type I SM), promotes colocalization of SM-bound CD300d3 to the cross-linked high-affinity IgE receptor and enhances IgE-dependent mast cell degranulation. The IgE-dependent anaphylactic responses are consistently enhanced by type I SM. However, the same responses are attenuated by CD300d3 deficiency, by interfering with the SM-CD300d3 interaction, or by treatment with vesicles containing ceramide or SM recognized by both CD300d3 and CD300f (type II SM). Overall, mast cell- and IgE-dependent anaphylaxis in mice is regulated by the binding of specific sphingolipids present in tissues to activating CD300d3 versus inhibitory CD300f.