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

J Allergy Clin Immunol. 2020 Nov;146(5):1152-1164.e13. doi: 10.1016/j.jaci.2020.03.004. Epub 2020 Mar 19.


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.

Keywords: Asthma; G proteins; PGE2; aspirin sensitivity; aspirin-exacerbated respiratory disease; regulators of G protein signaling protein.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aspergillosis / metabolism*
  • Aspergillus fumigatus / immunology*
  • Asthma, Aspirin-Induced / metabolism*
  • Bronchial Spasm
  • Cells, Cultured
  • Dinoprostone / biosynthesis
  • Female
  • Humans
  • Lung / pathology*
  • Male
  • Mice
  • Mice, Knockout
  • Muscle, Smooth / metabolism*
  • Muscle, Smooth / pathology
  • Prostaglandin-E Synthases / genetics
  • RGS Proteins / genetics
  • RGS Proteins / metabolism*
  • Respiratory Mucosa / metabolism*
  • Signal Transduction


  • RGS Proteins
  • RGS4 protein
  • Prostaglandin-E Synthases
  • Ptges protein, mouse
  • Dinoprostone