Lung IL-33 overexpression does not cause inflammation, but increases allergen sensitivity and disrupts lung morphogenesis

IL-33 is an IL-1 cytokine family member that promotes inflammatory responses via activation of many immune cell types. IL-33 is expressed in epithelial barrier tissues such as lung epithelium under both resting and inflammatory conditions. Secreted IL-33 plays an important role in type 2 innate immunity and adaptive immune responses. To characterize the roles of IL-33 in tissue and immune homeostasis in lung epithelium, we generated a novel transgenic mouse in which IL-33 was overexpressed only in lung epithelial cells driven by the tetracycline-sensitive Club cell secretory protein (CCSP) promoter. When IL-33 expression was induced in adult mice, overexpression of IL-33 protein approximately 3-fold above normal levels produced no pathological or immunological changes in the lungs. However, these animals developed significant increases in innate type 2 immune responses when exposed to natural or model allergens. When IL-33 expression was induced in pre- and post-natal mice, these mice had increased mortality, which was accompanied by lung hemorrhage and lung lobe malformation without detectable signs of inflammation and immune responses. Furthermore, IL-33 transgenic mice that survived to adulthood exhibited simplified and enlarged alveoli resembling bronchopulmonary dysplasia. Correspondingly, the epithelial cells from IL-33 transgenic mice displayed altered expression of genes involved in tissue and hematological system development. These data indicate dual effects of IL-33 overexpression depending on the developmental stage of the lungs, namely impairment of lung morphogenesis in the neonatal period and heightened sensitivity of innate type 2 immunity in adult mice.