FcεR1-expressing nociceptors trigger allergic airway inflammation

Background: Lung nociceptor neurons amplify immune cell activity and mucus metaplasia in response to an inhaled allergen challenge in sensitized mice. Objective: We sought to identify the cellular mechanisms by which these sensory neurons are activated subsequent to allergen exposure. Methods: We used calcium microscopy and electrophysiologic recording to assess whether vagal neurons directly respond to the model allergen ovalbumin (OVA). Next, we generated the first nociceptor-specific Fc epsilon R1 gamma knockdown (TRPV1(Cre)::Fc epsilon R1 gamma(fl/fl)) mice to assess whether this targeted invalidation would affect the severity of allergic inflammation in response to allergen challenges. Results: Lung-innervating jugular nodose complex ganglion neurons express the high-affinity IgE receptor Fc epsilon R1, the levels of which increase in OVA-sensitized mice. Fc epsilon R1 gamma-expressing vagal nociceptor neurons respond directly to OVA complexed with IgE with depolarization, action potential firing, calcium influx, and neuropeptide release. Activation of vagal neurons by IgE-allergen immune complexes, through the release of substance P from their peripheral terminals, directly amplifies T(H)2 cell influx and polarization in the airways. Allergic airway inflammation is decreased in TRPV1(Cre)::Fc epsilon R1 gamma(fl/fl) mice and in Fc epsilon R1 alpha(-/-) mice into which bone marrow has been transplanted. Finally, increased in vivo circulating levels of IgE following allergen sensitization enhances the responsiveness of Fc epsilon R1 to immune complexes in both mouse jugular nodose complex ganglion neurons and human induced pluripotent stem cell-derived nociceptors. Conclusions: Allergen sensitization triggers a feedforward inflammatory loop between IgE-producing plasma cells, Fc epsilon R1-expressing vagal sensory neurons, and T(H)2 cells, which helps to both initiate and amplify allergic airway inflammation. These data highlight a novel target for reducing allergy, namely, Fc epsilon R1 gamma expressed by nociceptors.