Neutrophil extracellular traps promote ΔNp63+ basal cell hyperplasia in chronic rhinosinusitis

Background: Neutrophil extracellular traps (NETs) are observed in chronic rhinosinusitis (CRS), although their role remains unclear. Objectives: This study aimed to investigate the influence of NETs on the CRS epithelium. Methods: Forty-five sinonasal biopsy specimens were immunofluorescence-stained to identify NETs and p63⁺ basal stem cells. Investigators treated human nasal epithelial cells with NETs and studied them with immunofluorescence staining, Western blotting, and quantitative real-time PCR. NET inhibitors were administered to a murine neutrophilic nasal polyp model. Results: NETs existed in tissues in patients with CRS with nasal polyps, especially in noneosinophilic nasal polyp tissues. p63⁺ basal cell expression had a positive correlation with the release of NETs. NETs induced the expansion of Ki-67⁺p63⁺ cells. We found that ΔNp63, an isoform of p63, was mainly expressed in the nasal epithelium and controlled by NETs. Treatment with deoxyribonuclease (DNase) I or Sivelestat (NET inhibitors) prevented the overexpression of ΔNp63+ epithelial stem cells and reduced polyp formation. Conclusions: These results reveal that NETs are implicated in CRS pathogenesis via basal cell hyperplasia. This study suggests a novel possibility of treating CRS by targeting NETs.