Shinji Toki1, Kasia Goleniewska1, Sara Reiss1, Jian Zhang1, Melissa H Bloodworth2, Matthew T Stier2, Weisong Zhou1, Dawn C Newcomb3, Lorraine B Ware3, Gregg D Stanwood4, Aurelio Galli5, Kelli L Boyd2, Kevin D Niswender6, R Stokes Peebles7. 1. Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, Tenn. 2. Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, Tenn. 3. Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, Tenn; Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, Tenn. 4. Department of Biomedical Sciences and Center for Brain Repair, Florida State University, Tallahassee, Fla. 5. Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tenn; Vanderbilt Brain Institute, Vanderbilt University School of Medicine, Nashville, Tenn. 6. Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tenn; Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, Tenn; Division of Diabetes, Endocrinology, and Metabolism, Vanderbilt University School of Medicine, Nashville, Tenn; Vanderbilt Brain Institute, Vanderbilt University School of Medicine, Nashville, Tenn. Electronic address: kevin.niswender@vanderbilt.edu. 7. Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, Tenn; Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, Tenn; Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, Tenn. Electronic address: stokes.peebles@vanderbilt.edu.
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.
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.
Authors: Dinah Foer; Patrick E Beeler; Jing Cui; Elizabeth W Karlson; David W Bates; Katherine N Cahill Journal: Am J Respir Crit Care Med Date: 2021-04-01 Impact factor: 21.405