Xie, X.; Wang, P.; Jin, M.; Wang, Y.; Qi, L.; Wu, C.; Guo, S.; Li, C.; Zhang, X.; Yuan, Y.; Ma, X.; Liu, F.; Liu, W.; Liu, H.; Duan, C.; Ye, P.; Li, X.; Larry, B.; Zhao, W.; Feng, X.

Neutrophilic inflammation contributes to multiple chronic inflammatory airway diseases, including asthma and chronic rhinosinusitis with nasal polyps (CRSwNP), and is associated with an unfavorable prognosis. Here, using single-cell RNA sequencing (scRNA-seq) to profile human nasal mucosa obtained from the inferior turbinates, middle turbinates, and nasal polyps of CRSwNP patients, we identified two IL-1 signaling-induced cell subsets - LY6D+ club cells and IDO1+ fibroblasts - that promote neutrophil recruitment by respectively releasing S100A8/A9 and CXCL1/2/3/5/6/8 into inflammatory regions. IL-1beta, a pro-inflammatory cytokine involved in IL-1 signaling, induces the transdifferentiation of LY6D+ club cells and IDO1+ fibroblasts from primary epithelial cells and fibroblasts, respectively. In an LPS-induced neutrophilic CRSwNP mouse model, blocking IL-1beta activity with a receptor antagonist significantly reduced the numbers of LY6D+ club cells and IDO1+ fibroblasts and mitigated nasal inflammation. This study reveals the roles of two cell subsets in neutrophil recruitment and demonstrates an IL-1-based intervention for mitigating neutrophilic inflammation in CRSwNP.