IL-33-induced neutrophilic inflammation and NETosis underlie rhinovirus-triggered exacerbations of asthma

Bodie Curren, Tufael Ahmed, Daniel R. Howard, Md Ashik Ullah, Ismail Sebina, Ridwan B. Rashid, Md Al Amin Sikder, Patricia Namubiru, Alec Bissell, Sylvia Ngo, David J. Jackson, Marie Toussaint, Michael R. Edwards, Sebastian L. Johnston, Henry J. McSorley, Simon Phipps (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)
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Abstract

Rhinovirus-induced neutrophil extracellular traps (NETs) contribute to acute asthma exacerbations; however, the molecular factors that trigger NETosis in this context remain ill-defined. Here, we sought to implicate a role for IL-33, an epithelial cell-derived alarmin rapidly released in response to infection. In mice with chronic experimental asthma (CEA), but not naïve controls, rhinovirus inoculation induced an early (1 day post infection; dpi) inflammatory response dominated by neutrophils, neutrophil-associated cytokines (IL-1α, IL-1β, CXCL1), and NETosis, followed by a later, type-2 inflammatory phase (3–7 dpi), characterised by eosinophils, elevated IL-4 levels, and goblet cell hyperplasia. Notably, both phases were ablated by HpARI (Heligmosomoides polygyrus Alarmin Release Inhibitor), which blocks IL-33 release and signalling. Instillation of exogenous IL-33 recapitulated the rhinovirus-induced early phase, including the increased presence of NETs in the airway mucosa, in a PAD4-dependent manner. Ex vivo IL-33-stimulated neutrophils from mice with CEA, but not naïve mice, underwent NETosis and produced greater amounts of IL-1α/β, IL-4, and IL-5. In nasal samples from rhinovirus-infected people with asthma, but not healthy controls, IL-33 levels correlated with neutrophil elastase and dsDNA. Our findings suggest that IL-33 blockade ameliorates the severity of an asthma exacerbation by attenuating neutrophil recruitment and the downstream generation of NETs.

Original languageEnglish
Pages (from-to)671-684
Number of pages14
JournalMucosal Immunology
Volume16
Issue number5
Early online date26 Jul 2023
DOIs
Publication statusPublished - Oct 2023

Keywords

  • Asthma
  • HpARI
  • IL-33
  • NETosis
  • PAD4
  • ST2
  • dsDNA
  • eosinophil
  • neutrophil
  • rhinovirus

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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