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

TY - JOUR

T1 - IL-33-induced neutrophilic inflammation and NETosis underlie rhinovirus-triggered exacerbations of asthma

AU - Curren, Bodie

AU - Ahmed, Tufael

AU - Howard, Daniel R.

AU - Ashik Ullah, Md

AU - Sebina, Ismail

AU - Rashid, Ridwan B.

AU - Al Amin Sikder, Md

AU - Namubiru, Patricia

AU - Bissell, Alec

AU - Ngo, Sylvia

AU - Jackson, David J.

AU - Toussaint, Marie

AU - Edwards, Michael R.

AU - Johnston, Sebastian L.

AU - McSorley, Henry J.

AU - Phipps, Simon

N1 - Copyright: © 2023. Published by Elsevier Inc.

PY - 2023/10

Y1 - 2023/10

N2 - 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.

AB - 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.

KW - Asthma

KW - HpARI

KW - IL-33

KW - NETosis

KW - PAD4

KW - ST2

KW - dsDNA

KW - eosinophil

KW - neutrophil

KW - rhinovirus

U2 - 10.1016/j.mucimm.2023.07.002

DO - 10.1016/j.mucimm.2023.07.002

M3 - Article

C2 - 37506849

SN - 1933-0219

VL - 16

SP - 671

EP - 684

JO - Mucosal Immunology

JF - Mucosal Immunology

IS - 5

ER -