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

Gordon S. Wong, Jamie L. Redes, Nariman Balenga, Morgan McCullough, Nathalie Fuentes, Ameya Gokhale, Cynthia Koziol-White, Joseph A. Jude, Laura A. Madigan, Eunice C. Chan, William H. Jester, Sabrina Biardel, Nicolas Flamand, Reynold A. Panettieri, Kirk M. Druey

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Background: Allergens elicit host production of mediators acting on G-protein–coupled receptors 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 after the ingestion of aspirin and other nonsteroidal anti-inflammatory drugs, a disorder termed aspirin-exacerbated respiratory disease. This condition may result in part from abnormal dependence on the bronchoprotective actions of PGE2. Objective: We sought to understand the functions of regulator of G protein signaling 4 (RGS4), a cytoplasmic protein expressed in airway smooth muscle and bronchial epithelium that regulates the activity of G-protein–coupled receptors, in asthma. Methods: We examined RGS4 expression in human lung biopsies by immunohistochemistry. We assessed airways hyperresponsiveness (AHR) and lung inflammation in germline and airway smooth muscle–specific Rgs4−/− mice and in mice treated with an RGS4 antagonist after challenge with Aspergillus fumigatus. We examined the role of RGS4 in nonsteroidal anti-inflammatory drug–associated bronchoconstriction by challenging aspirin-exacerbated respiratory disease–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 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.

Original languageEnglish (US)
Pages (from-to)1152-1164.e13
JournalJournal of Allergy and Clinical Immunology
Volume146
Issue number5
DOIs
StatePublished - Nov 2020

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

Keywords

  • Asthma
  • G proteins
  • PGE2
  • aspirin sensitivity
  • aspirin-exacerbated respiratory disease
  • regulators of G protein signaling protein

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