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Aeroallergen-induced IL-33 predisposes to respiratory virus–induced asthma by dampening antiviral immunity

Published:April 25, 2016DOI:https://doi.org/10.1016/j.jaci.2016.02.039

      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-α and IFN-λ 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-α 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.

      Key words

      Abbreviations used:

      AEC (Airway epithelial cell), AHR (Airway hyperreactivity), ASM (Airway smooth muscle), BALF (Bronchoalveolar lavage fluid), CRE (Cockroach extract), HDM (House dust mite), ILC (Innate lymphoid cell), IL1RL1 (IL-1 receptor-like 1), IRAK (IL-1 receptor–associated kinase 1), ISG (Interferon-stimulated gene), pDC (Plasmacytoid dendritic cell), pfu (Plaque-forming unit), PVM (Pneumonia virus of mice), RSV (Respiratory syncytial virus), TLR (Toll-like receptor), vLRI (Viral lower respiratory tract infection)
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