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

Yue Li; Li-Hong Chang; Wei-Qiang Huang; Hong-Wei Bao; Xia Li; Xiao-Hong Chen; Hao-Tian Wu; Zhou-Zhou Yao; Zi-Zhen Huang; Samuel E Weinberg; De-Yu Fang; Ya-Na Zhang; Ge-Hua Zhang

doi:10.1016/j.jaci.2022.02.031

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. Epub 2022 Mar 26.

Authors

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: zhangyn95@mail.sysu.edu.cn.
⁴ Department of Otolaryngology-Head and Neck Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China. Electronic address: zhanggeh@mail.sysu.edu.cn.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Caspases / metabolism
Chronic Disease
Humans
Interleukin-17* / metabolism
MAP Kinase Signaling System
NLR Family, Pyrin Domain-Containing 3 Protein / metabolism
Nasal Mucosa / metabolism
Nasal Polyps* / pathology
Pyroptosis*
Receptors, Glucocorticoid / metabolism
Sinusitis* / pathology
Steroids

Substances

IL17A protein, human
Interleukin-17
NLR Family, Pyrin Domain-Containing 3 Protein
Receptors, Glucocorticoid
Steroids
Caspases