Journal
JOURNAL OF IMMUNOLOGY
Volume 204, Issue 6, Pages 1650-1660Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1900234
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Funding
- Flight Attendant Medical Research Institute
- National Institute of General Medical Sciences [P20GM130555, 5P30GM110760]
- National Institute of Environmental Health Sciences [R01ES030125]
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Cystic fibrosis is characterized by dehydration of the airway surface liquid layer with persistent mucus obstruction. Th2 immune responses are often manifested as increased mucous cell density (mucous cell metaplasia) associated with mucus obstruction. IL-33 is a known inducer of Th2 immune responses, but its roles in mucus obstruction and related phenotypes in a cystic fibrosis-like lung disease model (i.e., Scnn1b-Tg-positive [Tg+]) mouse, remain unclear. Accordingly, IL-33 knockout (IL-33(KO)) Tg+ mice were examined and compared with IL-33 heterozygous (IL-33(HET)) Tg+ mice. As compared with IL-33(HET)/Tg+ mice, IL-33(KO)/Tg+ mice had complete absence of bronchoalveolar lavage fluid eosinophilia, accompanied with significant reduction in bronchoalveolar lavage fluid concentration of IL-5, a cytokine associated with eosinophil differentiation and recruitment, and IL-4, a major Th2 cytokine. As compared with IL-33(HET)/Tg+ mice, IL-33(KO)/Tg+ mice had significantly reduced levels of Th2-associated gene signatures (Slc26a4, Clcal, Retnla, and Chi3l4), along with complete loss of intracellular mucopolysaccharide staining in the airway epithelium. As compared with IL-33(HET)/Tg+ mice, although the IL-33(KO)/Tg+ mice had significantly reduced levels of MUC5AC protein expression, they showed no reduction in the degree of mucus obstruction, MUC5B protein expression, bacterial burden, and neonatal mortality. Interestingly, the histological features, including subepithelial airway inflammation and alveolar space enlargement, were somewhat exaggerated in IL-33(KO)/Tg+ mice compared with IL-33(HET)/Tg+ mice. Taken together, our data indicate that although IL-33 modulates Th2 inflammatory responses and MUC5AC protein production, mucus obstruction is not dependent on IL-33.
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