Sensory Neurons Initiate Tuft Cell-Dependent Sinonasal Allergic Inflammation via Substance P
The precise role and potential interactions of tuft cells with trigeminal sinonasal neurons in the context of allergic disease remain largely unexplored and unclear. This study investigated the impact of intranasal administration of house dust mite or fungal allergens on these cells and sought to understand the mechanisms underpinning the allergic response. We observed that these allergens incited a significant expansion in tuft cells, eosinophilia, sneezing, Type 2 immune responses, and elevated release of neuropeptides. Strikingly, mice devoid of tuft cells exhibited an absence of these responses, notwithstanding the persistence of eosinophilia and elevated neuropeptide levels. Ablation of Transient Receptor Potential Channel Vanilloid 1 (TRPV1)+ neurons prevented allergen-evoked tuft cell expansion and eosinophilia without affecting ILC2 and CD4+ Th2 cell recruitment. In addition, exposure of naïve TG neurons to allergen evoked calcium influx and neuropeptide release, but only Substance P (SP) adaptively increased upon repetitive allergen exposure. We found that SP not only guided tuft cell lineage commitment, but also initiated allergic inflammation. To substantiate this, we targeted the SP receptor, neurokinin 1, through ablation or inhibition. This led to a reversal of allergen-induced sneezing, tuft cell expansion, and eosinophilia, thereby emphasizing the critical role of SP and its receptor in Type 2 immunity. Based on our findings, we put forth the hypothesis that sinonasal nociceptors detect protease-containing allergens and adaptively secrete SP. This then acts as a key driver for tuft cell expansion and the early features of Type 2 immunity. This novel understanding of the mechanistic underpinnings of allergic responses opens the door for further research and potential therapeutic interventions in allergic disease.
Immunology and Infectious Disease, Neuroscience and Neurobiology
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