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

Suha Lim; Roza Khalmuratova; Yun Young Lee; Yi Sook Kim; Mingyu Lee; Na Kyeong Lee; Se-Na Kim; Young Bin Choy; Chun Gwon Park; Dae Woo Kim; Hyun-Woo Shin

doi:10.1016/j.jaci.2023.11.016

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

J Allergy Clin Immunol. 2024 Mar;153(3):705-717.e11. doi: 10.1016/j.jaci.2023.11.016. Epub 2023 Nov 22.

Authors

Suha Lim¹, Roza Khalmuratova², Yun Young Lee³, Yi Sook Kim¹, Mingyu Lee¹, Na Kyeong Lee⁴, Se-Na Kim⁵, Young Bin Choy³, Chun Gwon Park⁴, Dae Woo Kim⁶, Hyun-Woo Shin⁷

Affiliations

¹ Obstructive Upper airway Research (OUaR) Laboratory, Department of Pharmacology, Seoul National University College of Medicine, Seoul, Korea; Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, Korea; Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
² Obstructive Upper airway Research (OUaR) Laboratory, Department of Pharmacology, Seoul National University College of Medicine, Seoul, Korea.
³ Department of Biomedical Engineering, Seoul National University College of Medicine, Seoul, Korea.
⁴ Department of Biomedical Engineering, SKKU Institute for Convergence, Sungkyunkwan University (SKKU), Suwon, Korea; Department of Intelligent Precision Healthcare Convergence, SKKU Institute for Convergence, Sungkyunkwan University (SKKU), Suwon, Korea.
⁵ Department of Research and Development Center, MediArk Inc, Cheongju, Korea; Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University College of Medicine, Seoul National University Boramae Medical Center, Seoul, Korea.
⁶ Sensory Organ Research Institute, Seoul National University Medical Research Center, Seoul, Korea; Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University College of Medicine, Seoul National University Boramae Medical Center, Seoul, Korea.
⁷ Obstructive Upper airway Research (OUaR) Laboratory, Department of Pharmacology, Seoul National University College of Medicine, Seoul, Korea; Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, Korea; Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea; Sensory Organ Research Institute, Seoul National University Medical Research Center, Seoul, Korea; Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University Hospital, Seoul, Korea. Electronic address: charlie@snu.ac.kr.

PMID: 38000697
DOI: 10.1016/j.jaci.2023.11.016

Abstract

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.

Keywords: Chronic rhinosinusitis; hyperplasia; nasal polyps; neutrophil extracellular traps; ΔNp63.

MeSH terms

Animals
Chronic Disease
Extracellular Traps*
Humans
Hyperplasia / pathology
Mice
Nasal Mucosa / pathology
Nasal Polyps* / pathology
Rhinitis* / pathology
Rhinosinusitis*
Sinusitis* / pathology