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

Lynch, Jason P., Werder, Rhiannon B., Simpson, Jennifer, Loh, Zhixuan, Zhang, Vivian, Haque, Ashraful, Spann, Kirsten, Sly, Peter D., Mazzone, Stuart B., Upham, John W. and Phipps, Simon (2016) Aeroallergen-induced IL-33 predisposes to respiratory virus–induced asthma by dampening antiviral immunity. Journal of Allergy and Clinical Immunology, 138 5: 1326-1337. doi:10.1016/j.jaci.2016.02.039

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Author Lynch, Jason P.
Werder, Rhiannon B.
Simpson, Jennifer
Loh, Zhixuan
Zhang, Vivian
Haque, Ashraful
Spann, Kirsten
Sly, Peter D.
Mazzone, Stuart B.
Upham, John W.
Phipps, Simon
Title Aeroallergen-induced IL-33 predisposes to respiratory virus–induced asthma by dampening antiviral immunity
Journal name Journal of Allergy and Clinical Immunology   Check publisher's open access policy
ISSN 1097-6825
0091-6749
Publication date 2016-11-01
Year available 2016
Sub-type Article (original research)
DOI 10.1016/j.jaci.2016.02.039
Open Access Status File (Author Post-print)
Volume 138
Issue 5
Start page 1326
End page 1337
Total pages 12
Place of publication Philadelphia, PA, United States
Publisher Mosby
Language eng
Subject 2723 Immunology and Allergy
2403 Immunology
Abstract 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.
Formatted abstract
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.
Keyword Antiviral
IL-33
Interferon
Plasmacytoid dendritic cell
Pneumonia virus of mice
Respiratory syncytial virus
Type 2 innate lymphoid cell
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

 
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