PNAS | September 12, 2017

Nguyen LP, Al-Sawalha NA, Parra S, Pokkunuri I, Omoluabi O, Okulate AA, Windham Li E, Hazen M, Gonzalez-Granado JM, Daly CJ, McGrath JC, Tuvim MJ, Knoll BJ, Dickey BF and Bond RA

Proceedings of the National Academy of Sciences of the United States of America. 2017;114:E9163-e9171.

DOI: https://doi.org/10.1073/pnas.1710196114

This study was peformed using a Simoa® Homebrew assay.

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.