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IL-17A mediates pyroptosis via the ERK pathway and contributes to steroid resistance in CRSwNP

Yue Li1, Li-Hong Chang1, Wei-Qiang Huang1

  • 1Department of Otolaryngology-Head and Neck Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.

The Journal of Allergy and Clinical Immunology
|March 29, 2022
PubMed
Abstract

Insights

Interleukin-17A (IL-17A) promotes pyroptosis in human nasal epithelial cells (hNECs) via the ERK-NLRP3/caspase-1 pathway. This process contributes to steroid resistance in chronic rhinosinusitis with nasal polyps (CRSwNP).

Area of Science:

  • Immunology
  • Cell Biology
  • Pathology

Background:

  • Pyroptosis, a pro-inflammatory cell death, is implicated in various diseases, but its specific role in epithelial cells remains unclear.
  • Understanding the molecular drivers of pyroptosis in airway epithelium is crucial for developing targeted therapies.

Purpose of the Study:

  • To investigate the role and underlying mechanisms of IL-17A in human nasal epithelial cell (hNEC) pyroptosis.
  • To explore the contribution of IL-17A-induced pyroptosis to steroid resistance in chronic rhinosinusitis with nasal polyps (CRSwNP).

Main Methods:

  • Quantitative RT-PCR, immunohistochemistry, and immunofluorescence were used to assess biomarker expression in sinonasal mucosa.
  • Electron microscopy visualized pyroptotic ultrastructure, while functional assays and ELISA quantified IL-17A effects on hNECs.
  • RNA sequencing and Western blotting identified signaling pathways involved in IL-17A-induced pyroptosis.

Main Results:

  • IL-17A and pyroptosis biomarkers (NLRP3, caspase-1, gasdermin D, IL-1β) were upregulated in CRSwNP patients.
  • IL-17A treatment induced pyroptosis in hNECs via the ERK-NLRP3/caspase-1 pathway, increasing IL-1β and IL-18 secretion.
  • IL-17A-induced pyroptosis impaired glucocorticoid receptor homeostasis, leading to steroid resistance.

Conclusions:

  • Elevated IL-17A drives hNEC pyroptosis through the ERK-NLRP3/caspase-1 pathway in CRSwNP.
  • This pyroptosis contributes to glucocorticoid resistance by disrupting glucocorticoid receptor balance.
Keywords:
Epithelial cellsIL-17ANLRP3 inflammasomepyroptosissteroid resistance

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