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

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• 作者：Jason P. Lynch ; PhD^a ; ^&lowast ; ; Rhiannon B. Werder ; B Biomed Sci (Hons)^a ; ^&lowast ; ; Jennifer Simpson ; B Biomed Sci (Hons)^a ; Zhixuan Loh ; B Biomed Sci (Hons)^a ; Vivian Zhang ; PhD^a ; Ashraful Haque ; PhD^b ; Kirsten Spann ; PhD^c ; ^d ; Peter D. Sly ; MD ; PhD^d ; ^e ; Stuart B. Mazzone ; PhD^a ; John W. Upham ; MD ; PhD^d ; ^f ; Simon Phipps ; PhD^a ; ^d ; ^{s.phipps@uq.edu.au" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Pneumonia virus of mice ; IL-33 ; type 2 innate lymphoid cell ; antiviral ; respiratory syncytial virus ; interferon ; plasmacytoid dendritic cell
• 刊名：Journal of Allergy and Clinical Immunology
• 出版年：2016
• 出版时间：November 2016
• 年：2016
• 卷：138
• 期：5
• 页码：1326-1337
• 全文大小：1179 K

文摘

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 m>Pneumovirusm> 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 m>in vivom> and m>in vitrom>, 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.