Neuron-dependent tuft cell expansion initiates sinonasal allergic Type 2 inflammation.

It is unknown whether interactions between tuft cells and trigeminal sinonasal neurons contribute to allergic disease. Intranasal administration of house dust mite or fungal allergens induced tuft cell expansion, eosinophilia, sneezing, Type 2 responses, and neuropeptide release. Mice lacking tuft cells lost these responses but retained eosinophilia and elevated neuropeptides. Ablation of Transient Receptor Potential Channel Vanilloid 1 (TRPV1)+ neurons prevented allergen-evoked tuft cell expansion and eosinophilia without affecting ILC2 and T H 2 cell recruitment. Exposure of naïve TG neurons to allergen evoked calcium influx and neuropeptide release, but only Substance P (SP) adaptively increased upon repetitive allergen exposure. SP instructed tuft cell lineage commitment and initiated allergic inflammation. Ablation or inhibition of the SP receptor, neurokinin 1, reversed allergen-induced sneezing, tuft cell expansion, and eosinophilia. We propose that sinonasal nociceptors detect protease-containing allergens and adaptively secrete SP to drive tuft cell expansion and early features of Type 2 immunity.