Glucagon-like peptide-1 receptor signaling attenuates RSV-induced type 2 responses and immunopathology

Abstract

Abstract Glucagon-like peptide-1 receptor (GLP-1R) agonists are a well-accepted and safe treatment for Type II diabetes. Although GLP-1R agonists mainly act to potentiate insulin and suppress glucagon secretion, recent evidence suggests that GLP-1R signaling also has anti-inflammatory effects. Severe RSV-associated illness is partially caused by type 2-associated immunopathology. We hypothesized that GLP-1R signaling inhibits type 2-mediated immunopathology during infection with RSV 12/12-6, a strain of RSV that was isolated from a hospitalized infant with severe lower respiratory tract infection and bronchiolitis. We show here that GLP-1R agonist treatment decreased airway inflammation, airway reactivity, and airway mucus production in RSV 12/12-6-infected mice. GLP-1R agonist treatment decreased total lung IL-13 and IL-33 levels, with concurrent decreases in lung IL-13-producing group 2 innate lymphoid cell (ILC2), CD4+ Th2 cell, and basophil numbers as well as IL-33-producing epithelial cells. The GLP-1R agonist prevented airway inflammation, and did not impact viral load, anti-viral interferon and antibody production during secondary RSV infection. Relative to the respective mock-infected groups, RSV-infected GLP-1R agonist treated mice did not have increased weight loss compared to vehicle treated mice. A phenome-wide association study (PheWAS) identified a link between GLP-1R signaling and acute bronchitis and bronchiolitis in humans. These studies demonstrate that GLP-1R signaling protects against type 2-mediated immunopathology during RSV infection. GLP-1R agonists are the first known FDA-approved agents to inhibit IL-33 and may represent a novel treatment strategy for RSV bronchiolitis.