| First Author | Nguyen LP | Year | 2017 |
| Journal | Proc Natl Acad Sci U S A | Volume | 114 |
| Issue | 43 | Pages | E9163-E9171 |
| PubMed ID | 29073113 | Mgi Jnum | J:256927 |
| Mgi Id | MGI:6095543 | Doi | 10.1073/pnas.1710196114 |
| Citation | Nguyen LP, et al. (2017) beta2-Adrenoceptor signaling in airway epithelial cells promotes eosinophilic inflammation, mucous metaplasia, and airway contractility. Proc Natl Acad Sci U S A 114(43):E9163-E9171 |
| abstractText | The mostly widely used bronchodilators in asthma therapy are beta2-adrenoreceptor (beta2AR) agonists, but their chronic use causes paradoxical adverse effects. We have previously determined that beta2AR activation is required for expression of the asthma phenotype in mice, but the cell types involved are unknown. We now demonstrate that beta2AR 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 beta2AR 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 beta2AR signaling on resident lung cells modulates the asthma phenotype. Labeling with a fluorescent beta2AR ligand shows the receptors are highly expressed in airway epithelium. In beta2AR(-/-) mice, transgenic expression of beta2ARs 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 (betaarr-2(-/-)) attenuates the asthma phenotype as in beta2AR(-/-) mice. In contrast to eosinophilic inflammation, neutrophilic inflammation was not promoted by beta2AR signaling. Together, these results suggest beta2ARs on airway epithelial cells promote the asthma phenotype and that the proinflammatory pathway downstream of the beta2AR involves betaarr-2. These results identify beta2AR 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. |
