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

Abstract

The mostly widely used bronchodilators in asthma therapy are β₂-adrenoreceptor (β₂AR) agonists, but their chronic use causes paradoxical adverse effects. We have previously determined that β₂AR activation is required for expression of the asthma phenotype in mice, but the cell types involved are unknown. We now demonstrate that β₂AR 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 β₂AR 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 β₂AR signaling on resident lung cells modulates the asthma phenotype. Labeling with a fluorescent β₂AR ligand shows the receptors are highly expressed in airway epithelium. In β₂AR^-/- mice, transgenic expression of β₂ARs 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 β-arrestin-2 (βarr-2^-/-) attenuates the asthma phenotype as in β₂AR^-/- mice. In contrast to eosinophilic inflammation, neutrophilic inflammation was not promoted by β₂AR signaling. Together, these results suggest β₂ARs on airway epithelial cells promote the asthma phenotype and that the proinflammatory pathway downstream of the β₂AR involves βarr-2. These results identify β₂AR 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.