SummaryBackgroundClinical and experimental analyses have identified a central role for IgE/FcεRI/mast cells in promoting IgE‐mediated anaphylaxis. Recent data from human studies suggest that bacterial infections can alter susceptibility to anaphylaxis.ObjectiveWe examined the effect of LPS exposure on the induction of IgE‐mast cell (MC) mediated reactions in mice.MethodsC57BL/6 WT, tlr4^−/− and IL10^−/− mice were exposed to LPS, and serum cytokines (TNF and IL‐10) were measured. Mice were subsequently treated with anti‐IgE, and the symptoms of passive IgE‐mediated anaphylaxis, MC activation, Ca²⁺‐mobilization and the expression of FcεRI on peritoneal MCs were quantitated.ResultsWe show that LPS exposure of C57BL/6 WT mice constraints IgE‐MC–mediated reactions. LPS‐induced suppression of IgE‐MC–mediated responses was TLR‐4‐dependent and associated with increased systemic IL‐10 levels, decreased surface expression of FcεRI on MCs and loss of sensitivity to IgE activation. Notably, LPS‐induced desensitization of MCs was short term with MC sensitivity to IgE reconstituted within 48 hours, which was associated with recapitulation of FcεRI expression on the MCs. Mechanistic analyses revealed a requirement for IL‐10 in LPS‐mediated decrease in MC FcεRI surface expression.Conclusions & Clinical RelevanceCollectively, these studies suggest that LPS‐induced IL‐10 promotes the down‐regulation of MC surface FcεRI expression and leads to desensitization of mice to IgE‐mediated reactions. These studies indicate that targeting of the LPS‐TLR‐4‐IL‐10 pathway may be used as a therapeutic approach to prevent adverse IgE‐mediated reactions.