|Title||RGS4 promotes allergen- and aspirin-associated airway hyper-responsiveness by inhibiting PGE2 biosynthesis.|
|Publication Type||Journal Article|
|Year of Publication||2020|
|Authors||Wong, GS, Redes, JL, Balenga, N, McCullough, M, Fuentes, N, Gokhale, A, Koziol-White, C, Jude, JA, Madigan, LA, Chan, EC, Jester, WH, Biardel, S, Flamand, N, Panettieri, RA, Druey, KM|
|Journal||J Allergy Clin Immunol|
|Date Published||2020 Mar 18|
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.
|Alternate Journal||J. Allergy Clin. Immunol.|