In:
Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 114, No. 43 ( 2017-10-24)
Abstract:
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.
Type of Medium:
Online Resource
ISSN:
0027-8424
,
1091-6490
DOI:
10.1073/pnas.1710196114
Language:
English
Publisher:
Proceedings of the National Academy of Sciences
Publication Date:
2017
detail.hit.zdb_id:
209104-5
detail.hit.zdb_id:
1461794-8
SSG:
11
SSG:
12