Eosinophil Peroxidase–associated PRKCB–CCL4/CCR5 Signaling in Chronic Rhinosinusitis with Nasal Polyps

Abstract Eosinophil-derived effector molecules may contribute to persistent mucosal inflammation in chronic rhinosinusitis with nasal polyps (CRSwNP), but their effects on nasal epithelial responses remain incompletely understood. This study examined whether eosinophil peroxidase (EPX) contributes to CRSwNP-associated epithelial inflammation. Data-independent acquisition–based quantitative proteomics was performed on nasal tissues from 69 patients with CRSwNP and 39 control subjects. Protein–protein interaction and weighted co-expression network analyses were used to identify candidate molecules, and EPX expression was validated in nasal tissues. The effects of EPX were examined through adeno-associated virus–mediated EPX knockdown in a murine CRSwNP model and recombinant EPX stimulation of human nasal epithelial cells, with or without PKCβ inhibition. Proteomic analysis identified 1,850 differentially expressed proteins, including 760 upregulated and 1,090 downregulated proteins. EPX was markedly upregulated in human CRSwNP tissues and murine nasal mucosa and was associated with eosinophilic inflammatory features. In mice, EPX knockdown attenuated nasal mucosal pathology and inflammatory cell infiltration and reduced IL-4, IL-5, IgE, PRKCB, CCL4, and CCR5 levels. In nasal epithelial cells, EPX increased PRKCB, CCL4, and CCR5 expression in a concentration-dependent manner, whereas PKCβ inhibition partially attenuated EPX-induced CCL4 and CCR5 upregulation. EPX is associated with eosinophilic inflammation in CRSwNP and may contribute to nasal epithelial inflammatory responses involving the PRKCB–CCL4/CCR5 network. The mechanistic relevance of this network to CRSwNP warrants further investigation.