Division of Allergic Diseases, Department of Medicine, Mayo Clinic, Rochester, Minnesota, United States of America.
Division of Allergy, Asthma, and Clinical Immunology, Department of Medicine, Mayo Clinic, Scottsdale, Arizona, United States of America.
PLoS One. 2021 May 28;16(5):e0252199. doi: 10.1371/journal.pone.0252199. eCollection 2021.
Early life respiratory insults, such as viral infections or hyperoxia, often increase asthma susceptibility later in life. The mechanisms underlying this increased susceptibility are not fully understood. IL-33 has been shown to be critically involved in allergic airway diseases. IL-33 expression in the neonatal lung can be increased by various respiratory insults associated with asthma development. Therefore, we investigated whether and how early life increases in IL-33 impact allergic airway responses later in life. Using a novel IL-33 transgenic mouse model, in which full-length IL-33 was inducible overexpressed in lung epithelial cells, we transiently upregulated lung IL-33 expression in neonatal mice for one week. After resting for 4-6 weeks, mice were intranasally exposed to a single-dose of recombinant IL-33 or the airborne allergen Alternaria. Alternatively, mice were exposed to Alternaria and ovalbumin multiple times for one month. We found that a transient increase in IL-33 expression during the neonatal period promoted IL-5 and IL-13 production when mice were later exposed to a single-dose of IL-33 or Alternaria in adulthood. However, increased IL-33 expression during the neonatal period did not affect airway inflammation, type 2 cytokine production, lung mucus production, or antigen-specific antibody responses when adult mice were exposed to Alternaria and ovalbumin multiple times. These results suggest that transient increased IL-33 expression early in life may have differential effects on allergic airway responses in later life, preferentially affecting allergen-induced acute type 2 cytokine production.
早期生活中的呼吸道损伤，如病毒感染或高氧，通常会增加以后生活中哮喘的易感性。这种易感性增加的机制尚未完全阐明。IL-33 已被证明在过敏性气道疾病中起关键作用。各种与哮喘发生相关的呼吸道损伤可增加新生儿肺中的 IL-33 表达。因此，我们研究了生命早期 IL-33 的增加是否以及如何影响以后生活中的过敏性气道反应。使用一种新型的 IL-33 转基因小鼠模型，其中全长 IL-33 在肺上皮细胞中可诱导过表达，我们在新生小鼠中短暂上调肺 IL-33 表达一周。休息 4-6 周后，小鼠通过鼻腔内给予单次剂量的重组 IL-33 或空气过敏原链格孢。或者，小鼠接受链格孢和卵清蛋白多次暴露一个月。我们发现，在新生儿期 IL-33 表达的短暂增加会促进成年后再次暴露于单次剂量的 IL-33 或链格孢时 IL-5 和 IL-13 的产生。然而，当成年小鼠多次暴露于链格孢和卵清蛋白时，新生儿期增加的 IL-33 表达并不影响气道炎症、2 型细胞因子产生、肺粘液产生或抗原特异性抗体反应。这些结果表明，生命早期短暂增加的 IL-33 表达可能对以后生活中的过敏性气道反应产生不同的影响，优先影响变应原诱导的急性 2 型细胞因子产生。
