DUOX1 mediates persistent epithelial EGFR activation, mucous cell metaplasia, and airway remodeling during allergic asthma.
Chronic inflammation with mucous metaplasia and airway remodeling are hallmarks of allergic asthma, and these outcomes have been associated with enhanced expression and activation of EGFR signaling. Here, we demonstrate enhanced expression of EGFR ligands such as amphiregulin as well as constitutive EGFR activation in cultured nasal epithelial cells from asthmatic subjects compared with nonasthmatic controls and in lung tissues of mice during house dust mite-induced (HDM-induced) allergic inflammation. EGFR activation was associated with cysteine oxidation within EGFR and the nonreceptor tyrosine kinase Src, and both amphiregulin production and oxidative EGFR activation were diminished by pharmacologic or genetic inhibition of the epithelial NADPH oxidase dual oxidase 1 (DUOX1). DUOX1 deficiency also attenuated several EGFR-dependent features of HDM-induced allergic airway inflammation, including neutrophilic inflammation, type 2 cytokine production (IL-33, IL-13), mucous metaplasia, subepithelial fibrosis, and central airway resistance. Moreover, targeted inhibition of airway DUOX1 in mice with previously established HDM-induced allergic inflammation, by intratracheal administration of DUOX1-targeted siRNA or pharmacological NADPH oxidase inhibitors, reversed most of these outcomes. Our findings indicate an important function for DUOX1 in allergic inflammation related to persistent EGFR activation and suggest that DUOX1 targeting may represent an attractive strategy in asthma management.
Departments of Pathology and Laboratory Medicine and.
Aida
A
Habibovic
Departments of Pathology and Laboratory Medicine and.
Milena
M
Hristova
Departments of Pathology and Laboratory Medicine and.
David E
DE
Heppner
Departments of Pathology and Laboratory Medicine and.
Karamatullah
K
Danyal
Department of Medicine, Vermont Lung Center, Robert Larner, M.D. College of Medicine, University of Vermont, Burlington, Vermont, USA.
Jennifer L
JL
Ather
Departments of Pathology and Laboratory Medicine and.
Yvonne Mw
YM
Janssen-Heininger
Department of Medicine, Vermont Lung Center, Robert Larner, M.D. College of Medicine, University of Vermont, Burlington, Vermont, USA.
Charles G
CG
Irvin
Department of Medicine, Vermont Lung Center, Robert Larner, M.D. College of Medicine, University of Vermont, Burlington, Vermont, USA.
Matthew E
ME
Poynter
Department of Medicine, Vermont Lung Center, Robert Larner, M.D. College of Medicine, University of Vermont, Burlington, Vermont, USA.
Lennart K
LK
Lundblad
Department of Medicine, Vermont Lung Center, Robert Larner, M.D. College of Medicine, University of Vermont, Burlington, Vermont, USA.
Anne E
AE
Dixon
Department of Physiology and "Lendület" Peroxidase Enzyme Research Group, Semmelweis University, Budapest, Hungary.
Miklos
M
Geiszt
Departments of Pathology and Laboratory Medicine and.
Albert
A
van der Vliet
D056151:Airway Remodeling; D066258:Amphiregulin / Q000378:metabolism; D000818:Animals; D001249:Asthma / Q000473:pathology*; D016207:Cytokines / Q000378:metabolism; D000074623:Dual Oxidases / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D020397:Goblet Cells / Q000166:cytology*; D006801:Humans; D007249:Inflammation; D008297:Male; D008679:Metaplasia / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL
D066258:Amphiregulin; D016207:Cytokines; D000074623:Dual Oxidases; C431513:DUOX1 protein, human; C519130:Duox1 protein, mouse; C512478:EGFR protein, human; D066246:ErbB Receptors