RGS4 promotes allergen- and aspirin-associated airway hyper-responsiveness by inhibiting PGE2 biosynthesis

Abstract Background Allergens elicit host production of mediators acting on G-protein coupled receptors (GPCRs) to regulate airway tone. Among these is prostaglandin E2 (PGE2), which, in addition to its role as a bronchodilator, has anti-inflammatory actions. Some patients with asthma develop bronchospasm following ingestion of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs), a disorder termed aspirin-exacerbated respiratory disease (AERD). This condition may result in part from abnormal dependence on the bronchoprotective actions of prostaglandin E2 (PGE2). Objective We sought to understand the functions of Regulator of G Protein Signaling 4 (RGS4), a cytoplasmic protein expressed in airway smooth muscle (ASM) and bronchial epithelium that regulates activity of GPCRs, in asthma. Methods We examined RGS4 expression in human lung biopsies by immunohistochemistry. We assessed airways hyper-responsiveness (AHR) and lung inflammation in germline and ASM-specific Rgs4−/− mice and in mice treated with an RGS4 antagonist following challenge with Aspergillus fumigatus. We examined the role of RGS4 in NSAID-associated bronchoconstriction by challenging AERD-like (ptges1-/-) mice with aspirin. Results RGS4 expression in respiratory epithelium is increased in subjects with severe asthma. Allergen-induced AHR was unexpectedly diminished in Rgs4−/− mice, a finding associated with increased airway PGE2 levels. RGS4 modulated allergen-induced PGE2 secretion in human bronchial epithelial cells and prostanoid-dependent bronchodilation. The RGS4 antagonist CCG203769 attenuated AHR induced by allergen or aspirin challenge of wild type (WT) or ptges1-/- mice, respectively, in association with increased airway PGE2 levels. Conclusions RGS4 may contribute to the development of AHR by reducing airway PGE2 biosynthesis in allergen- and aspirin-induced asthma.