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

β 2 -Adrenoceptor signaling in airway epithelial cells promotes eosinophilic inflammation, mucous metaplasia, and airway contractility

β ₂ -Adrenoceptor signaling in airway epithelial cells promotes eosinophilic inflammation, mucous metaplasia, and airway contractility