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

  • J Allergy Clin Immunol. 2022 Aug;150(2):337-351. doi: 10.1016/j.jaci.2022.02.031.
Yue Li  1 ,  Li-Hong Chang  1 ,  Wei-Qiang Huang  1 ,  Hong-Wei Bao  1 ,  Xia Li  1 ,  Xiao-Hong Chen  1 ,  Hao-Tian Wu  1 ,  Zhou-Zhou Yao  1 ,  Zi-Zhen Huang  1 ,  Samuel E Weinberg  2 ,  De-Yu Fang  2 ,  Ya-Na Zhang  3 ,  Ge-Hua Zhang  4
Affiliations
  • 1. Department of Otolaryngology-Head and Neck Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
  • 2. Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, Ill.
  • 3. Department of Otolaryngology-Head and Neck Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China. Electronic address: [email protected].
  • 4. Department of Otolaryngology-Head and Neck Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China. Electronic address: [email protected].
PMID: 35346673 DOI: 10.1016/j.jaci.2022.02.031
Abstract

Background: Pyroptosis is closely related to inflammation. However, the molecular mechanisms and pathologic contributions of pyroptotic epithelial cell are not yet fully understood.

Objective: This study aimed to explore the function and molecular mechanisms of IL-17A on human nasal epithelial cell (hNEC) Pyroptosis.

Methods: The expression of pyroptosis-related biomarkers and IL-17A was assessed in sinonasal mucosa from control individuals, patients with chronic rhinosinusitis without nasal polyps, and patients with chronic rhinosinusitis with nasal polyps (CRSwNP) by using quantitative RT-PCR. Their localization was analyzed via immunohistochemistry and immunofluorescence. The ultrastructural characteristics of IL-17A-induced Pyroptosis in hNECs were visualized by using electron microscopy. IL-17A functional assays were performed on hNECs and airway epithelial cell lines. Cytokine levels were quantified via ELISA. The signaling pathways involved in IL-17A-induced Pyroptosis were studied via unbiased RNA Sequencing and Western blotting.

Results: The expression of IL-17A and the pyroptotic biomarkers NOD-like Receptor family, pyrin domain containing 3 (NLRP3), Caspase-1, gasdermin D, and IL-1β was increased in nasal mucosa from patients with CRSwNP compared with in those with chronic rhinosinusitis without nasal polyps and the control subjects. IL-17A was positively correlated and colocalized with the pyroptotic biomarkers. IL-17A treatment induced Pyroptosis in the hNECs and cell lines analyzed, primarily through the extracellular signal-regulated kinase (ERK)-NLRP3/Caspase-1 signaling pathway, and increased IL-1β and IL-18 secretion in hNECs. Moreover, IL-17A-induced Pyroptosis contributed to steroid resistance by affecting glucocorticoid receptor-α and glucocorticoid receptor-β expression, and the inhibition of pyroptotic proteins partially abolished IL-17A-induced steroid resistance in hNECs.

Conclusion: Elevated IL-17A level promotes Pyroptosis in hNECs through the ERK-NLRP3/Caspase-1 signaling pathway and contributes to glucocorticoid resistance by affecting Glucocorticoid Receptor homeostasis in patients with CRSwNP.

Keywords
Epithelial cells; IL-17A; NLRP3 inflammasome; pyroptosis; steroid resistance.
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