Glucagon-like peptide 1 signaling inhibits allergen-induced lung IL-33 release and reduces group 2 innate lymphoid cell cytokine production in vivo

J Allergy Clin Immunol. 2018 Nov;142(5):1515-1528.e8. doi: 10.1016/j.jaci.2017.11.043. Epub 2018 Jan 10.

Abstract

Background: IL-33 is one of the most consistently associated gene candidates for asthma identified by using a genome-wide association study. Studies in mice and in human cells have confirmed the importance of IL-33 in inducing type 2 cytokine production from both group 2 innate lymphoid cells (ILC2s) and TH2 cells. However, there are no pharmacologic agents known to inhibit IL-33 release from airway cells.

Objective: We sought to determine the effect of glucagon-like peptide 1 receptor (GLP-1R) signaling on aeroallergen-induced airway IL-33 production and release and on innate type 2 airway inflammation.

Methods: BALB/c mice were challenged intranasally with Alternaria extract for 4 consecutive days. GLP-1R agonist or vehicle was administered starting either 2 days before the first Alternaria extract challenge or 1 day after the first Alternaria extract challenge.

Results: GLP-1R agonist treatment starting 2 days before the first Alternaria extract challenge decreased IL-33 release in the bronchoalveolar lavage fluid and dual oxidase 1 (Duox1) mRNA expression 1 hour after the first Alternaria extract challenge and IL-33 expression in lung epithelial cells 24 hours after the last Alternaria extract challenge. Furthermore, GLP-1R agonist significantly decreased the number of ILC2s expressing IL-5 and IL-13, lung protein expression of type 2 cytokines and chemokines, the number of perivascular eosinophils, mucus production, and airway responsiveness compared with vehicle treatment. GLP-1R agonist treatment starting 1 day after the first Alternaria extract challenge also significantly decreased eosinophilia and type 2 cytokine and chemokine expression in the airway after 4 days of Alternaria extract challenge.

Conclusion: These results reveal that GLP-1R signaling might be a therapy to reduce IL-33 release and inhibit the ILC2 response to protease-containing aeroallergens, such as Alternaria.

Keywords: Alternaria; Glucagon-like peptide 1 receptor; IL-33; group 2 innate lymphoid cells; liraglutide.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Allergens / immunology
  • Alternaria / immunology
  • Animals
  • Asthma / immunology*
  • Cytokines / immunology
  • Dermatophagoides pteronyssinus / immunology
  • Eosinophilia / immunology
  • Female
  • Glucagon-Like Peptide 1 / immunology*
  • Glucagon-Like Peptide-1 Receptor / agonists
  • Glucagon-Like Peptide-1 Receptor / immunology*
  • Immunity, Innate
  • Interleukin-33 / immunology*
  • Lung / cytology
  • Lung / immunology
  • Lymphocytes / immunology
  • Mice, Inbred BALB C
  • Mice, Transgenic
  • Mucus / immunology
  • Signal Transduction

Substances

  • Allergens
  • Cytokines
  • Glp1r protein, mouse
  • Glucagon-Like Peptide-1 Receptor
  • Il33 protein, mouse
  • Interleukin-33
  • Glucagon-Like Peptide 1