Eosinophilic chronic rhinosinusitis with nasal polyps: Squamous metaplasia as an associated remodeling feature.

Abstract

Epithelial remodeling is a key pathologic feature of eosinophilic chronic rhinosinusitis with nasal polyps (eCRSwNP). Among the various remodeling patterns, squamous metaplasia remains an underrecognized component in eCRSwNP. This study aimed to systematically assess the prevalence of squamous metaplasia in eCRSwNP and explore its potential mechanisms. A total of 844 chronic rhinosinusitis with nasal polyps specimens were histologically reviewed to assess the prevalence of squamous metaplasia and compare rates between eCRSwNP and noneosinophilic (neCRSwNP) subtypes. RNA sequencing was used to profile related gene expression in controls, neCRSwNP, and eCRSwNP tissues, with reverse transcription quantitative PCR and immunofluorescence validation in an independent cohort. Nasal epithelial cells were cultured in an air-liquid interface (ALI) system, stimulated with IL-4/IL-13 and dupilumab to evaluate morphologic and molecular changes. Of the 844 chronic rhinosinusitis with nasal polyps samples, 132 (15.6%) showed squamous metaplasia, with higher prevalence in eCRSwNP (25.7%) compared to neCRSwNP (7.5%). Transcriptomic analysis revealed significantly elevated expression scores of keratinocyte differentiation-related genes in eCRSwNP, with KRT6A and KRT13 markedly upregulated. Cohort validation confirmed increased mRNA and protein levels of KRT6A, KRT13, filaggrin, p63, and Ki-67 in eCRSwNP, predominantly localized to the epithelium. In vitro, IL-4/IL-13 exposure induced squamous alterations in ALI cultures, characterized by increased expression of squamous differentiation markers and reduction in ciliated and secretory cell markers. These pathologic changes were attenuated by dupilumab treatment. Squamous metaplasia is a common but underappreciated epithelial remodeling feature in eCRSwNP. IL-4/IL-13 drive this pathologic shift, whereas dupilumab attenuates these changes, suggesting a role in preserving epithelial homeostasis beyond inflammation control.