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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 now sought to identify the cellular mechanisms by which these sensory neurons are activated upon allergen exposure.

METHODS: 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 (TRPV1Cre ::FcεR1γfl/fl ) mice to assess whether this targeted invalidation would impact the severity of allergic inflammation in response to allergen challenges.

RESULTS: 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 TH 2 cell influx and polarization in the airways. Allergic airway inflammation is decreased in TRPV1Cre ::FcεR1γfl/fl 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.

CONCLUSIONS: Allergen-sensitization triggers a feedforward inflammatory loop between IgE-producing plasma cells, FcεR1 expressing vagal sensory neurons, and TH 2 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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