Amphiregulin Mediates Epithelial Cell–Eosinophil Interactions and Amplifies Inflammation in Chronic Rhinosinusitis With Nasal Polyps

BACKGROUND: Eosinophils easily accumulate in the intra-epithelial layer and subepithelial regions in eosinophilic chronic rhinosinusitis with nasal polyps (ECRSwNP). While several factors influence the migration of eosinophils from peripheral blood to extravascular tissues, the triggers and role of eosinophils near the epithelial layer in CRSwNP remain unclear. METHODS: We examined interactions between eosinophils and epithelial cells using co-culture systems. We assessed the expression of amphiregulin (AREG) in CRSwNP epithelial cells and investigated its impact on epithelial barrier function, eosinophil activation, and migration. These effects were further validated in a CRSwNP mouse model treated with an AREG-blocking antibody. RESULTS: Co-culturing blood eosinophils and primary epithelial cells from CRSwNP patients decreased tight junction expression and increased eosinophil activation. Epithelial cells from ECRSwNP patients expressed higher levels of AREG than those from non-eosinophilic CRSwNP (non-ECRSwNP) patients, particularly in basal cells. As measured in the culture medium by ELISA, both blood eosinophils and primary epithelial cells automatically secreted AREG. Our in vitro experiments demonstrated that AREG impaired epithelial barrier function and facilitated eosinophil migration and activation. Confirmatory studies in a CRSwNP mouse model indicated that blocking AREG reduced the number of nasal polyp-like lesions, mucosal thickness, and eosinophil infiltration, while restoring the expression of tight junction proteins. CONCLUSION: The upregulation of AREG triggers eosinophil migration and mediates the interaction between epithelial cells and eosinophils, thereby enhancing chronic inflammation in CRSwNP. Our study highlights the therapeutic potential of anti-AREG antibodies in CRSwNP, offering a promising strategy for treating human eosinophilic sinus diseases.