| First Author | Yee MC | Year | 2018 |
| Journal | Am J Physiol Lung Cell Mol Physiol | Volume | 315 |
| Issue | 6 | Pages | L1042-L1057 |
| PubMed ID | 30335499 | Mgi Jnum | J:272113 |
| Mgi Id | MGI:6280210 | Doi | 10.1152/ajplung.00196.2018 |
| Citation | Yee MC, et al. (2018) Protease-activated receptor-2 signaling through beta-arrestin-2 mediates Alternaria alkaline serine protease-induced airway inflammation. Am J Physiol Lung Cell Mol Physiol 315(6):L1042-L1057 |
| abstractText | Alternaria alternata is a fungal allergen associated with severe asthma and asthma exacerbations. Similarly to other asthma-associated allergens, Alternaria secretes a serine-like trypsin protease(s) that is thought to act through the G protein-coupled receptor protease-activated receptor-2 (PAR2) to induce asthma symptoms. However, specific mechanisms underlying Alternaria-induced PAR2 activation and signaling remain ill-defined. We sought to determine whether Alternaria-induced PAR2 signaling contributed to asthma symptoms via a PAR2/beta-arrestin signaling axis, identify the protease activity responsible for PAR2 signaling, and determine whether protease activity was sufficient for Alternaria-induced asthma symptoms in animal models. We initially used in vitro models to demonstrate Alternaria-induced PAR2/beta-arrestin-2 signaling. Alternaria filtrates were then used to sensitize and challenge wild-type, PAR2(-/-) and beta-arrestin-2(-/-) mice in vivo. Intranasal administration of Alternaria filtrate resulted in a protease-dependent increase of airway inflammation and mucin production in wild-type but not PAR2(-/-) or beta-arrestin-2(-/-) mice. Protease was isolated from Alternaria preparations, and select in vitro and in vivo experiments were repeated to evaluate sufficiency of the isolated Alternaria protease to induce asthma phenotype. Administration of a single isolated serine protease from Alternaria, Alternaria alkaline serine protease (AASP), was sufficient to fully activate PAR2 signaling and induce beta-arrestin-2(-/-)-dependent eosinophil and lymphocyte recruitment in vivo. In conclusion, Alternaria filtrates induce airway inflammation and mucus hyperplasia largely via AASP using the PAR2/beta-arrestin signaling axis. Thus, beta-arrestin-biased PAR2 antagonists represent novel therapeutic targets for treating aeroallergen-induced asthma. |
