The physiological functions of mast cells remain largely an enigma. In the context of barrier damage, mast cells are integrated in type 2 immunity and, together with immunoglobulin E (IgE), promote allergic diseases. Allergic symptoms may, however, facilitate expulsion of allergens, toxins and parasites and trigger future antigen avoidance^1–3. Here, we show that antigen-specific avoidance behaviour in inbred mice^4,5 is critically dependent on mast cells; hence, we identify the immunological sensor cell linking antigen recognition to avoidance behaviour. Avoidance prevented antigen-driven adaptive, innate and mucosal immune activation and inflammation in the stomach and small intestine. Avoidance was IgE dependent, promoted by Th2 cytokines in the immunization phase and by IgE in the execution phase. Mucosal mast cells lining the stomach and small intestine rapidly sensed antigen ingestion. We interrogated potential signalling routes between mast cells and the brain using mutant mice, pharmacological inhibition, neural activity recordings and vagotomy. Inhibition of leukotriene synthesis impaired avoidance, but overall no single pathway interruption completely abrogated avoidance, indicating complex regulation. Collectively, the stage for antigen avoidance is set when adaptive immunity equips mast cells with IgE as a telltale of past immune responses. On subsequent antigen ingestion, mast cells signal termination of antigen intake. Prevention of immunopathology-causing, continuous and futile responses against per se innocuous antigens or of repeated ingestion of toxins through mast-cell-mediated antigen-avoidance behaviour may be an important arm of immunity.

PGE₂ has long been known as a potentiator of acute inflammation, but its mechanisms of action still remain to be defined. In this study, we employed inflammatory swelling induced in mice by arachidonate and PGE₂ as models and dissected the role and mechanisms of action of each EP receptor at the molecular level. Arachidonate- or PGE₂-induced vascular permeability was significantly reduced in EP3-deficient mice. Intriguingly, the PGE₂-induced response was suppressed by histamine H₁ antagonist treatment, histidine decarboxylase deficiency, and mast cell deficiency. The impaired PGE₂-induced response in mast cell–deficient mice was rescued upon reconstitution with wild-type mast cells but not with EP3-deficient mast cells. Although the number of mast cells, protease activity, and histamine contents in ear tissues in EP3-deficient mice were comparable to those in wild-type mice, the histamine contents in ear tissues were attenuated upon PGE₂ treatment in wild-type but not in EP3-deficient mice. Consistently, PGE₂–EP3 signaling elicited histamine release in mouse peritoneal and bone marrow–derived mast cells, and it exerted degranulation and IL-6 production in a manner sensitive to pertussis toxin and a PI3K inhibitor and dependent on extracellular Ca²⁺ ions. These results demonstrate that PGE₂ triggers mast cell activation via an EP3–G_i/o–Ca²⁺ influx/PI3K pathway, and this mechanism underlies PGE₂-induced vascular permeability and consequent edema formation.