IL-13 driven tuft cell hyperplasia is suppressed by retinoic acid in chronic rhinosinusitis with nasal polyps.

Tuft cells are specialized chemosensory epithelial cells that contribute to mucosal immunity, yet how their differentiation is regulated in human airway disease remains unclear. Chronic rhinosinusitis with nasal polyps(CRSwNP) features type 2 inflammation and expansion of sinonasal tuft cells, consistent with type 2 cytokine-driven epithelial remodeling. Using primary human sinonasal epithelial air-liquid interface cultures, we examined tuft cell differentiation across disease phenotypes. IL-13-induced expansion of POU2F3+ tuft cells and generated a BMX+ subset consistent with a mature or activated phenotype. These IL-13 activated cultures exhibited enhanced responsiveness to chemosensory ligands such as succinate and denatonium, indicating functional activation. Surprisingly, IL-13-driven sinonasal tuft cell differentiation occurred despite inhibition of STAT6 and ERK signaling, suggesting involvement of noncanonical pathways. Retinoic acid(RA) emerged as a selective regulator of tuft cell differentiation specifically in CRSwNP. RA did not alter STAT6 phosphorylation or canonical IL-13-responsive gene expression, indicating that RA suppresses tuft cell differentiation through distinct mechanisms. These findings highlight a noncanonical pathway of IL-13-mediated tuft cell expansion and identify retinoic acid as a context-dependent regulator of tuft cell differentiation in the airway. These findings demonstrate methods to regulate human sinonasal tuft cell differentiation across disease phenotypes, opening avenues for tuft cell-targeted therapeutic strategies.