Critical role of sensory neuronal TRPA1 signals in mediating cough hypersensitivity in allergic rhinitis

<bold>Background:</bold> Allergic rhinitis (AR) is a major cause of upper airway cough syndrome (UACS). Sensitization of airway sensory nerves is an important mechanisms in UACS. But it remains unclear which population of sensory neurons initiates the AR-related cough reflex. <bold>Objective:</bold> This study aimed to examine the pathogenic role and neuromodulatory mechanisms of transient receptor potential ankyrin 1 (TRPA1) in AR-related cough hypersensitivity. <bold>Methods:</bold> AR-related cough hypersensitivity model is established by repeated OVA sensitization and challenge. Episodes of cough and nasal symptom were counted. The concentrations of cytokines and the degree of leukocyte infiltration in nasal tissues were assessed. The expression of neuropeptides in nasal mucosa and trigeminal ganglia (TG) neurons was measured. <bold>Results:</bold> There was a significant increase in cough counts induced by citric acid and AITC challenges in WT-AR group, indicating the AR-related cough hypersensitivity model was constructed successfully. The genetic ablation of TRPA1 inhibited nasal eosinophil and neutrophil cells infiltration, reduced mucus production and cytokine levels, and ameliorate the cough counts (Fig 1). The knockdown of TRPA1 significantly decreases the expression of substance P(SP) and calcitonin gene-related peptide(CGRP) in nasal submucosa and TG neurons of AR mice. In addition, TRPA1-mediated nasal inflammation in AR mice acts through SP-neurokinin 1 receptor(NK1R) pathway(Fig 2). <bold>Conclusion:</bold> This study revealed for the first time that sensory neuronal TRPA1 signals mediate cough hypersensitivity in AR mice, and that neurogenic inflammation of the nasal trigeminal sensory nerve afferent pathway may be involved.