Glucagon-like Peptide-1 Receptor Pathway Attenuates Platelet Activation in Aspirin-Exacerbated Respiratory Disease

Author:

Foer Dinah12ORCID,Amin Taneem3,Nagai Jun12ORCID,Tani Yumi1ORCID,Feng Chunli12,Liu Tao12ORCID,Newcomb Dawn C.34,Lai Juying1,Hayashi Hiroaki1,Snyder William E.3,McGill Alanna1,Lin Anabel3,Laidlaw Tanya M.12ORCID,Niswender Kevin D.567,Boyce Joshua A.12ORCID,Cahill Katherine N.3ORCID

Affiliation:

1. *Division of Allergy and Clinical Immunology, Department of Medicine, Brigham and Women’s Hospital, Boston, MA

2. †Harvard Medical School, Boston, MA

3. ‡Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, TN

4. §Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, TN

5. ¶Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN

6. ‖United States Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN

7. #Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN

Abstract

Abstract Platelets are key contributors to allergic asthma and aspirin-exacerbated respiratory disease (AERD), an asthma phenotype involving platelet activation and IL-33–dependent mast cell activation. Human platelets express the glucagon-like peptide-1 receptor (GLP-1R). GLP-1R agonists decrease lung IL-33 release and airway hyperresponsiveness in mouse asthma models. We hypothesized that GLP-1R agonists reduce platelet activation and downstream platelet-mediated airway inflammation in AERD. GLP-1R expression on murine platelets was assessed using flow cytometry. We tested the effect of the GLP-1R agonist liraglutide on lysine-aspirin (Lys-ASA)–induced changes in airway resistance, and platelet-derived mediator release in a murine AERD model. We conducted a prospective cohort study comparing the effect of pretreatment with liraglutide or vehicle on thromboxane receptor agonist-induced in vitro activation of platelets from patients with AERD and nonasthmatic controls. GLP-1R expression was higher on murine platelets than on leukocytes. A single dose of liraglutide inhibited Lys-ASA–induced increases in airway resistance and decreased markers of platelet activation and recruitment to the lung in AERD-like mice. Liraglutide attenuated thromboxane receptor agonist-induced activation as measured by CXCL7 release in plasma from patients with AERD and CD62P expression in platelets from both patients with AERD (n = 31) and nonasthmatic, healthy controls (n = 11). Liraglutide, a Food and Drug Administration–approved GLP-1R agonist for treatment of type 2 diabetes and obesity, attenuates in vivo platelet activation in an AERD murine model and in vitro activation in human platelets in patients with and without AERD. These data advance the GLP-1R axis as a new target for platelet-mediated inflammation warranting further study in asthma.

Funder

HHS | NIH | National Heart, Lung, and Blood Institute

HHS | NIH | National Institute of Allergy and Infectious Diseases

Publisher

The American Association of Immunologists

Subject

Immunology,Immunology and Allergy

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