GLP-1 Receptor Signaling Differentially Modifies the Outcomes of Sterile vs Viral Pulmonary Inflammation in Male Mice

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.