IL-33 downregulates human IL-33 expression in the pulmonary vasculature during allergic airway inflammation

Abstract IL-33 is abundantly expressed in the human lung, where it is involved in pathogen defense, barrier homeostasis, and development of type 2 allergic responses. We recently identified a 5 kb region within a GWAS-defined segment that acts as an enhancer barrier element in vivo and in vitro. We showed that the asthma-associated SNP rs1888909, located within the 5 kb region, is associated with IL33 gene expression in human airway epithelial cells and IL-33 protein in human plasma. To study this human regulatory region in vivo, we engineered a novel IL33 reporter mouse containing the human 5kb regulatory element to reflect human IL33 expression. As expected, human and mouse IL33 reporters were primarily expressed in non-overlapping cell types: human IL33 reporter was mostly expressed in vascular and lymphatic endothelium, while mouse IL33 reporter was expressed in ATII epithelium. Interestingly, we demonstrate negative regulation of human IL33 in lung endothelium during house dust mite (HDM)-induced allergic airway inflammation, which was dependent on the human 5kb regulatory region. Similar downregulation of endothelium IL-33 was induced with only IL-33 treatment in vivo and in vitro. We found that this IL-33-induced negative feedback loop worked through the induction of cytoplasmic IL33 mRNA instability. Together, these data reveal the importance of the asthma-associated human 5kb enhancer element in regulating human IL33 expression in a cell type- and context-dependent manner.