Hypoxia Induces Lung Inflammation and Immunity by ILC2 through Stimulating Adrenomedullin from Epithelial Cells

Hypoxia contributes to airway inflammation and remodeling in several lung diseases; however, exactly how hypoxic pulmonary epithelium regulates allergic inflammation remains to be fully characterized. Here we report that conditional deletion of the E3 ubiquitin ligase VHL in lung epithelial cells resulted in exacerbated type 2 responses accompanied by selective increase of group 2 innate lymphoid cells (ILC2s) at steady state and following inflammation or helminth infection. Ablation of expression of the hypoxia-inducible factor 2 (HIF2a significantly reversed VHL-mediated ILC2 activation. VHL deficiency in lung epithelial cells caused the increased expression of the peptide hormone adrenomedullin (ADM), and our data suggest HIF2a controls Adm expression. ADM directly promoted ILC2 activation both in vitro and in vivo. Our findings indicate that the hypoxic response mediated by the VHL-HIF2a axis is critical for control of pulmonary type 2 responses by increasing ADM expression in lung epithelia causing ILC2 activation. Overall design: Lung bronchiolar epithelial mRNA profiles of WT and VHL conditional knockout mice