Lung nociceptor neurons amplify immune cell activity and mucus metaplasia in response to an inhaled allergen challenge in sensitized mice.
We now sought to identify the cellular mechanisms by which these sensory neurons are activated upon allergen exposure.
We used calcium microscopy and electrophysiological recording to assess whether vagal neurons directly respond to the model allergen ovalbumin (OVA). Next, we generated the first nociceptor specific FcεR1γ knockdown (TRPV1::FcεR1γ) mice to assess whether this targeted invalidation would impact the severity of allergic inflammation in response to allergen challenges.
Lung-innervating jugular nodose complex ganglion (JNC) neurons express the high-affinity IgE receptor FcεR1 and the levels of this receptor increase in OVA-sensitized mice. FcεR1γ-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 (SP) from their peripheral terminals, directly amplifies T2 cell influx and polarization in the airways. Allergic airway inflammation is decreased in TRPV1::FcεR1γ mice or in bone marrow-transplanted FcεR1α mice. Finally, increased in vivo circulating levels of IgE following allergen sensitization enhances the responsiveness of FcεR1 to immune complexes in both mouse JNC neurons and human iPSC-derived nociceptors.
Allergen-sensitization triggers a feedforward inflammatory loop between IgE-producing plasma cells, FcεR1 expressing vagal sensory neurons, and T2 cells, which helps both initiate and amplify allergic airway inflammation. These data highlight a novel target for reducing allergy; FcεR1γ expressed by nociceptors.

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