Protease-activated receptor-2 signaling through β-arrestin-2 mediates alternaria alkaline serine protease-induced airway inflammation

Michael C. Yee, Heddie L. Nichols, Danny Polley, Mahmoud Saifeddine, Kasturi Pal, Kyu Lee, Emma H. Wilson, Michael O. Daines, Morley D. Hollenberg, Scott Boitano, Kathryn A. Defea

Research output: Contribution to journalArticlepeer-review

25 Scopus citations


Al-ternaria alternata is a fungal allergen associated with severe asthma and asthma exacerbations. Similarly to other asthma-associated allergens, Alternaria secretes a serine-like trypsin pro-tease(s) that is thought to act through the G protein-coupled receptor protease-activated receptor-2 (PAR 2 ) to induce asthma symptoms. However, specific mechanisms underlying Alternaria-induced PAR 2 activation and signaling remain ill-defined. We sought to determine whether Alternaria-induced PAR 2 signaling contributed to asthma symptoms via a PAR 2 /β-arrestin signaling axis, identify the protease activity responsible for PAR 2 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 PAR 2 /β-arrestin-2 signaling. Alternaria filtrates were then used to sensitize and challenge wild-type, PAR 2 / and β-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 PAR 2 / or β-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 PAR 2 signaling and induce β-arrestin-2 / -dependent eosinophil and lymphocyte recruitment in vivo. In conclusion, Alternaria filtrates induce airway inflammation and mucus hyper-plasia largely via AASP using the PAR 2 /β-arrestin signaling axis. Thus, β-arrestin-biased PAR 2 antagonists represent novel therapeutic targets for treating aeroallergen-induced asthma.

Original languageEnglish (US)
Pages (from-to)L1042-L1057
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Issue number6
StatePublished - Dec 2018


  • Airway inflammation
  • Allergen-induced asthma
  • Alternaria alternata
  • Biased G protein-coupled receptor signaling
  • Protease-activated receptor-2
  • β-arrestin-signaling

ASJC Scopus subject areas

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology


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