GLP-1 Receptor Signaling Differentially Modifies the Outcomes of Sterile vs Viral Pulmonary Inflammation in Male Mice
Open accessAbstract
A number of disease states, including type 2 diabetes (T2D), are associated with an increased risk of pulmonary infection. Glucagon-like peptide-1 (GLP-1) receptor agonists are used to treat T2D and exert anti-inflammatory actions through a single, well-defined GLP-1 receptor (GLP-1R). Although highly expressed in the lung, little is known about the role of the GLP-1R in the context of pulmonary inflammation. Here we examined the consequences of gain or loss of GLP-1R activity in infectious and noninfectious lung inflammation. We studied wild-type mice treated with a GLP-1R agonist, and Glp1r–/– mice, in the setting of bleomycin-induced noninfectious lung injury and influenza virus infection. Loss of the GLP-1R attenuated the severity of bleomycin-induced lung injury, whereas activation of GLP-1R signaling increased pulmonary inflammation via the sympathetic nervous system. In contrast, GLP-1R agonism reduced the pathogen load in mice with experimental influenza virus infection in association with increased expression of intracellular interferon-inducible GTPases. Notably, the GLP-1 receptor agonist liraglutide improved the survival rate after influenza virus infection. Our results reveal context-dependent roles for the GLP-1 system in the response to lung injury. Notably, the therapeutic response of GLP-1R agonism in the setting of experimental influenza virus infection may have relevance for ongoing studies of GLP-1R agonism in people with T2D susceptible to viral lung injury.
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One-week treatment with 200 μg/kg liraglutide exacerbated bleomycin-induced lung injury in control but not Glp1r-/- mice, an effect prevented by cotreatment with atipamezole.
“Notably, a 1-week treatment with 200 μg/kg liraglutide exacerbated bleomycin-induced lung injury in control but not Glp1r–/– mice, an effect prevented by cotreatment with atipamezole, an α2-adrenergic receptor antagonist.”
From Antiinflammatory actions of glucagon-like peptide-1–based therapies beyond metabolic benefits (2025) · cites this paper as [77]
The Bleomycin-induced lung injury model section gives the 200 μg/kg liraglutide dose, and the sections on liraglutide-induced inflammation and sympathetic signaling report worsened injury and substantial attenuation with atipamezole. However, the Glp1r-/- section compares knockout and wild-type mice after bleomycin without reporting liraglutide treatment in the knockout mice. The cited results also describe liraglutide treatment for 0–2 days or 2 weeks, not the claimed one-week course, and say atipamezole reduced rather than fully prevented the adverse effects; page numbers were not available in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredIn situ hybridization has identified Glp1r expression in type 2 alveolar epithelial cells, which may contribute to Il6 and Ccl2 induction following bleomycin exposure.
“In situ hybridization has identified Glp1r expression in type 2 alveolar epithelial cells, which may contribute to Il6 and Ccl2 induction following bleomycin exposure (77).”
From Antiinflammatory actions of glucagon-like peptide-1–based therapies beyond metabolic benefits (2025) · cites this paper as [77]
In a bleomycin-induced model of lung injury, Glp1r-/- mice exhibited reduced weight loss and lowered lung Il6, Il1b, Ccl2, and Cxcl2 expression, although survival remained unchanged.
“In this model, Glp1r–/– mice exhibited reduced weight loss and lowered lung Il6, Il1b, Ccl2, and Cxcl2 expression, although survival remained unchanged (77).”
From Antiinflammatory actions of glucagon-like peptide-1–based therapies beyond metabolic benefits (2025) · cites this paper as [77]
Daily treatment with 200 μg/kg liraglutide downregulated Il6 and Ccl2 in the lungs of mice during the first 3 days after influenza infection.
“Similarly, daily treatment with 200 μg/kg liraglutide downregulated Il6 and Ccl2 in the lungs of mice during the first 3 days after influenza infection (77).”
From Antiinflammatory actions of glucagon-like peptide-1–based therapies beyond metabolic benefits (2025) · cites this paper as [77]
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References 62 · Cited by 29
Research works printed but not linked: 2
- [37]37. Akita University institutional repository system. Deposited November 9, 2020. http://hdl.handle.net/10295/00005149
- [53]53. Padro CJ, Sanders VM. Neuroendocrine regulation of inflam- mation. Semin Immunol. 2014;26(5):357-368.
- Authors
- Sato, T., Shimizu, T., Fujita, H., Imai, Y., Drucker, D. J., Seino, Y., & Yamada, Y.
- Affiliations
- Akita University (JP)
- National Institute of Biomedical Innovation, Health and Nutrition (JP)
- Mount Sinai Hospital (CA)
- Kansai Electric Power (Japan) (JP)
- Corresponding author
- Yamada, Yuichiro
- Venue
- Endocrinology
- Publisher
- The Endocrine Society
- Published
- 2020-10-30
- Volume
- 161
- Issue
- 12
- ISSN
- 0013-7227 (ISSN-L)
- 1945-7170
- PMC
- PMC7678414
- OpenAlex
- W3096077207
- Cited by
- 29
- References
- 62
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 3 · 2023: 6 · 2022: 3 · 2021: 7
- FWCI
- 3.02
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
- Locations
- Endocrinology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Japan Society for the Promotion of Science (18H03171)
- Japan Agency for Medical Research and Development (JP18ek0210111)
- Japan Association for Diabetes Education and Care
- Japan Foundation for Applied Enzymology
- Canadian Institutes of Health Research (154321)
- Novo Nordisk Foundation
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- GLP-1 receptor, GLP-1 receptor agonists, liraglutide, lung inflammation, bleomycin-induced lung injury, influenza, type 2 diabetes, sympathetic nervous system, interferon-inducible GTPases, anti-inflammatory signaling, sex differences
- MeSH terms
- Glucagon-Like Peptide-1 Receptor, Liraglutide, Glucagon-Like Peptide-1 Receptor Agonists, Animals, Bleomycin, Male, Orthomyxoviridae Infections, Pneumonia, Signal Transduction, Mice, Knockout, Mice, Incretins
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