Allergen-elicited signaling cascades in olfactory microvillous tuft cells

PROJECT SUMMARY: The nasal mucosa consists of two distinct compartments - olfactory neuroepithelium and respiratory epithelium. As such, the nose serves as both a respiratory and as a sensory organ. Among the epithelial cells strategically positioned at the apical surface at the site of interaction with the inhaled air in the olfactory and respiratory epithelium are two populations of specialized cells with shared core mediator profile but distinct receptor repertoire – the olfactory TRPM5+ microvillous cells (MVCs) and the respiratory solitary chemosensory cells (SCCs). While bitter taste receptors, bitter tasting bacterial metabolites and succinate are well defined ligands of respiratory tuft cells (tracheal brush and respiratory SCCs), the ligands and signaling pathways of olfactory TRPM5+ MVCs are less well defined. We recently found that TRPM5+ MVCs detect allergens and the danger signal ATP to generate proinflammatory mediators including cysteinyl leukotrienes and prostaglandins in an in vitro system. We also demonstrated that allergen recognition by the olfactory TRPM5+ MVCs initiates an aberrant response of stem cell proliferation in the absence of profound inflammation in the olfactory mucosa. Here, we will determine how the TRPM5+ MVCs contribute to the integrated airway epithelial response to allergens and the determinants of pro- vs anti-inflammatory programs directed by these new members of the tuft cell family. In Aim 1, we will define the signaling components engaged upon allergen detection by TRPM5+ MVCs. In Aim 2, we will determine how signals detected by TRPM5+ MVCs are propagated in the olfactory neuroepithelium, and the mediators (eicosanoids, epithelial cytokines, acetylcholine) generated by TRPM5+ MVCs or immediately downstream of them. Findings here will clarify how the olfactory TRPM5+ MVC tuft cells detect allergens, the consequences of their activation, and possible therapeutic targets.