Cadherin-26 Contributes to Intraepithelial Eosinophil and Neutrophil Infiltration in Chronic Rhinosinusitis with Nasal Polyps.

Abstract

Chronic rhinosinusitis with nasal polyps (CRSwNP) features marked infiltration of diverse inflammatory cells. Cadherin-26 (CDH26) is an adhesion molecule associated with eosinophilic inflammation, but its role in CRSwNP remains undefined. To investigate the expression, mechanisim, and function of CDH26 in CRSwNP. Bulk and single-cell RNA sequencing and immunohistochemistry of human nasal tissues profiled CDH26 expression, localization, and its association with immune cells and inflammatory pathways in CRSwNP. Nasal epithelial cells were stimulated with cytokines to examine CDH26 expression, and were transfected to evaluate CDH26's impact on JAK-STAT signaling. Adhesion and survival assays were conducted with isolated eosinophils and neutrophils. CDH26^-/- mice were used to establish a CRSwNP model to determine CDH26's role in disease development. CDH26 was elevated in eosinophilic CRSwNP (ECRSwNP) compared with control and non-eosinophilic CRSwNP (NECRSwNP) and correlated with intraepithelial infiltration of both eosinophils and neutrophils. Single-cell analysis showed its epithelial localization and co-expression with IL13RA1/STAT6 in basal cells. CDH26 was induced by IL-4/IL-13 via JAK-STAT signaling and, in turn, enhanced STAT6 phosphorylation. CDH26 mediated epithelial adhesion of eosinophils and neutrophils via integrin α4 (ITGA4) and enhanced their survival in vitro. CDH26^-/- mice showed attenuated nasal polyp-like lesion formation and reduction in the infiltration of eosinophils, neutrophils, mast cells, and T cell subsets. CDH26 is a type 2-inducible epithelial molecule that functions as an inflammatory mediator in CRSwNP by modulating JAK-STAT signaling and promoting eosinophil and neutrophil retention, thereby linking epithelial dysfunction to sustained inflammation and may represent a potential therapeutic target.