期刊
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
卷 138, 期 5, 页码 1326-1337出版社
MOSBY-ELSEVIER
DOI: 10.1016/j.jaci.2016.02.039
关键词
Pneumonia virus of mice; IL-33; type 2 innate lymphoid cell; antiviral; respiratory syncytial virus; interferon; plasmacytoid dendritic cell
资金
- Rebecca L. Cooper Medical Research Foundation
- Australian Infectious Disease Research Excellence Award
- Australian Research Council Future Fellowship
Background: Frequent viral lower respiratory infections in early life are an independent risk factor for asthma onset. This risk and the development of persistent asthma are significantly greater in children who later become sensitized. Objective: We sought to elucidate the pathogenic processes that underlie the synergistic interplay between allergen exposures and viral infections. Methods: Mice were inoculated with a murine-specific Pneumovirus species (pneumonia virus of mice [PVM]) and exposed to low-dose cockroach extract (CRE) in early and later life, and airway inflammation, remodeling, and hyperreactivity assessed. Mice were treated with anti-IL-33 or apyrase to neutralize or block IL-33 release. Results: PVM infection or CRE exposure alone did not induce disease, whereas PVM/CRE coexposure acted synergistically to induce the hallmark features of asthma. CRE exposure during viral infection in early life induced a biphasic IL-33 response and impaired IFN-alpha and IFN-lambda production, which in turn increased epithelial viral burden, airway smooth muscle growth, and type 2 inflammation. These features were ameliorated when CRE-induced IL-33 release was blocked or neutralized, whereas substitution of CRE with exogenous IL-33 recapitulated the phenotype observed in PVM/CRE-coexposed mice. Mechanistically, IL-33 downregulated viperin and interferon regulatory factor 7 gene expression and rapidly degraded IL-1 receptor-associated kinase 1 expression in plasmacytoid dendritic cells both in vivo and in vitro, leading to Toll-like receptor 7 hyporesponsiveness and impaired IFN-alpha production. Conclusion: We identified a hitherto unrecognized function of IL-33 as a potent suppressor of innate antiviral immunity and demonstrate that IL-33 contributes significantly to the synergistic interplay between respiratory virus and allergen exposures in the onset and progression of asthma.
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