Endogenous Glucagon-Like Peptide-1 Receptor and Glucose-Dependent Insulinotropic Polypeptide Receptor Signaling Inhibits Aeroallergen-Induced Innate Airway Inflammation

Allergy. 2024 Dec;79(12):3373-3384. doi: 10.1111/all.16402. Epub 2024 Nov 19.

Abstract

Background: Anti-inflammatory effects of incretin signaling through the glucagon-like peptide-1 receptor (GLP-1R) and the glucose-dependent insulinotropic polypeptide receptor (GIPR) in mice have been reported. Therefore, we hypothesized that signaling through the endogenous GLP-1R and the GIPR individually decreases allergic airway inflammation and that the combination of GLP-1R and GIPR signaling together additively inhibits allergen-induced lung and airway inflammation.

Methods: WT (C57BL/6J), GLP-1R knockout (KO), GIPR KO, and GLP-1R/GIPR double KO (DKO) mice were challenged intranasally with Alternaria alternata extract (Alt-Ext) or vehicle to evaluate the impact of signaling through these receptors on the innate allergen-induced inflammatory response that is primarily driven by group 2 innate lymphoid cells (ILC2).

Results: Alt-Ext-induced IL-33 release in the bronchoalveolar lavage fluid (BALF) was not different between the mouse strains, but thymic stromal lymphopoietin (TSLP) was significantly increased in GLP-1R/GIPR DKO mice challenged with Alt-Ext compared to the other strains. Furthermore, Alt-Ext-induced protein expression of IL-5, IL-13, CCL11, and CCL24 in the lung homogenates, the number of eosinophils, lymphocytes, and neutrophils in the BALF, and the number of lung GATA3+ ILC2 were significantly increased in GLP-1R/GIPR DKO mice compared to the other 3 strains. Furthermore, ICAM-1 expression on lung epithelial cells was increased in GLP-1R/GIPR DKO mice challenged with Alt-Ext compared to the other 3 strains.

Conclusions: Deficiency of both GLP-1R and GIPR signaling together increased TSLP release, ILC2 activation, and early type 2 innate immune responses to aeroallergen exposure. Combined GLP-1R and GIPR signaling should be explored for the treatment of asthma.

Keywords: GIPR; GLP‐1R; allergy; asthma; incretin.

MeSH terms

  • Allergens* / immunology
  • Alternaria / immunology
  • Animals
  • Bronchoalveolar Lavage Fluid / immunology
  • Cytokines / metabolism
  • Disease Models, Animal
  • Glucagon-Like Peptide-1 Receptor* / metabolism
  • Immunity, Innate*
  • Lung / immunology
  • Lung / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout*
  • Receptors, Gastrointestinal Hormone* / metabolism
  • Signal Transduction*

Substances

  • Allergens
  • Glucagon-Like Peptide-1 Receptor
  • gastric inhibitory polypeptide receptor
  • Receptors, Gastrointestinal Hormone
  • Cytokines