期刊
ALLERGY
卷 75, 期 8, 页码 2005-2019出版社
WILEY
DOI: 10.1111/all.14241
关键词
asthma; IL-1 beta; IL-25; IL-33; type 2 innate lymphoid cell
资金
- NIAID NIH HHS [R01 AI120526] Funding Source: Medline
- NIH HHS [R01 AI120526] Funding Source: Medline
Background: Early-life wheezing-associated respiratory infection with human rhinovirus (RV) is associated with asthma development. RV infection of 6-day-old immature mice causes mucous metaplasia and airway hyperresponsiveness which is associated with the expansion of IL-13-producing type 2 innate lymphoid cells (ILC2s) and dependent on IL-25 and IL-33. We examined regulation of this asthma-like phenotype by IL-1 beta. Methods: Six-day-old wild-type or NRLP3-/- mice were inoculated with sham or RVA1B. Selected mice were treated with IL-1 receptor antagonist (IL-1RA), anti-IL-1 beta, or recombinant IL-1 beta. Results: Rhinovirus infection induced Il25, Il33, Il4, Il5, Il13, muc5ac, and gob5 mRNA expression, ILC2 expansion, mucus metaplasia, and airway hyperresponsiveness. RV also induced lung mRNA and protein expression of pro-IL-1 beta and NLRP3 as well as cleavage of caspase-1 and pro-IL-1 beta, indicating inflammasome priming and activation. Lung macrophages were a major source of IL-1 beta. Inhibition of IL-1 beta signaling with IL-1RA, anti-IL-1 beta, or NLRP3 KO increased RV-induced type 2 cytokine immune responses, ILC2 number, and mucus metaplasia, while decreasing IL-17 mRNA expression. Treatment with IL-1 beta had the opposite effect, decreasing IL-25, IL-33, and mucous metaplasia while increasing IL-17 expression. IL-1 beta and IL-17 each suppressed Il25, Il33, and muc5ac mRNA expression in cultured airway epithelial cells. Finally, RVinfected 6-day-old mice showed reduced IL-1 beta mRNA and protein expression compared to mature mice. Conclusion: Macrophage IL-1 beta limits type 2 inflammation and mucous metaplasia following RV infection by suppressing epithelial cell innate cytokine expression. Reduced IL-1 beta production in immature animals provides a mechanism permitting asthma development after early-life viral infection.
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