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

[Display omitted] 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 relea...

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Published in:Mucosal immunology 2023-10, Vol.16 (5), p.671-684
Main Authors: Curren, Bodie, Ahmed, Tufael, Howard, Daniel R, Ashik Ullah, Md, Sebina, Ismail, Rashid, Ridwan B, Al Amin Sikder, Md, Namubiru, Patricia, Bissell, Alec, Ngo, Sylvia, Jackson, David J, Toussaint, Marie, Edwards, Michael R., Johnston, Sebastian L, McSorley, Henry J., Phipps, Simon
Format: Article
Language:English
Subjects:
Alarmins
Animals
Asthma
Extracellular Traps
Humans
Inflammation
Interleukin-33
Interleukin-4
Mice
Neutrophils
Rhinovirus
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Summary:[Display omitted] 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.
ISSN:1933-0219
1935-3456
DOI:10.1016/j.mucimm.2023.07.002