β2-Adrenoceptor signaling in airway epithelial cells promotes eosinophilic inflammation, mucous metaplasia, and airway contractility

The mostly widely used bronchodilators in asthma therapy are beta(2)-adrenoreceptor (beta(2)AR) agonists, but their chronic use causes paradoxical adverse effects. We have previously determined that beta(2)AR activation is required for expression of the asthma pheno-type in mice, but the cell types involved are unknown. We now demonstrate that beta(2)AR signaling in the airway epithelium is sufficient to mediate key features of the asthmatic responses to IL-13 in murine models. Our data show that inhibition of beta(2)AR signaling with an aerosolized antagonist attenuates airway hyperresponsiveness (AHR), eosinophilic inflammation, and mucus-production responses to IL-13, whereas treatment with an aerosolized agonist worsens these phenotypes, suggesting that beta(2)AR signaling on resident lung cells modulates the asthma phenotype. Labeling with a fluorescent beta(2)AR ligand shows the receptors are highly expressed in airway epithelium. In beta(2)AR(-/-) mice, transgenic expression of beta(2)ARs only in airway epithelium is sufficient to rescue IL-13-induced AHR, inflammation, and mucus production, and transgenic overexpression in WT mice exacerbates these phenotypes. Knockout of beta-arrestin-2 (beta arr-2(-/-)) attenuates the asthma phenotype as in beta(2)AR(-/-) mice. In contrast to eosinophilic inflammation, neutrophilic inflammation was not promoted by beta(2)AR signaling. Together, these results suggest beta(2)ARs on airway epithelial cells promote the asthma phenotype and that the proinflammatory pathway downstream of the beta(2)AR involves beta arr-2. These results identify beta(2)AR signaling in the airway epithelium as capable of controlling integrated responses to IL-13 and affecting the function of other cell types such as airway smooth muscle cells.