WITHDRAWN: Neuron-dependent tuft cell expansion initiates sinonasal allergic Type 2 inflammation

Abstract

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 TH2 cell recruitment. Exposure of naive 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.