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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 language | English |
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Pages (from-to) | 671-684 |
Number of pages | 14 |
Journal | Mucosal Immunology |
Volume | 16 |
Issue number | 5 |
Early online date | 26 Jul 2023 |
DOIs | |
Publication status | Published - 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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- 2 Finished
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MICA: Modulation of IL-33-dependent Responses Using Parasite Products (Transfer)
McSorley, H. (Investigator)
1/02/20 → 30/06/22
Project: Research