GLP-1R Agonists Modulate Enteric Immune Responses Through the Intestinal Intraepithelial Lymphocyte GLP-1R

Abstract

Obesity and diabetes are characterized by increased inflammation reflecting disordered control of innate immunity. We reveal a local intestinal intraepithelial lymphocyte (IEL)-GLP-1 receptor (GLP-1R) signaling network that controls mucosal immune responses. Glp1r expression was enriched in intestinal IEL preparations and copurified with markers of Tαβ and Tγδ IELs, the two main subsets of intestinal IELs. Exendin-4 increased cAMP accumulation in purified IELs and reduced the production of cytokines from activated IELs but not from splenocytes ex vivo. These actions were mimicked by forskolin, absent in IELs from Glp1r−/− mice, and attenuated by the GLP-1R agonist exendin (9-39) consistent with a GLP-1R–dependent mechanism of action. Furthermore, Glp1r−/− mice exhibited dysregulated intestinal gene expression, an abnormal representation of microbial species in feces, and enhanced sensitivity to intestinal injury following administration of dextran sodium sulfate. Bone marrow transplantation using wild-type C57BL/6 donors normalized expression of multiple genes regulating immune function and epithelial integrity in Glp1r−/− recipient mice, whereas acute exendin-4 administration robustly induced the expression of genes encoding cytokines and chemokines in normal and injured intestine. Taken together, these findings define a local enteroendocrine-IEL axis linking energy availability, host microbial responses, and mucosal integrity to the control of innate immunity.

The Cardiovascular Biology of Glucagon-like Peptide-1

“…A local gut L cell-T cell network has been revealed through studies identifying expression of a functional endogenous GLP-1R expressed within intestinal intraepithelial lymphocytes (IELs) (Yusta et al, 2015). Basal expression of cytoprotective and anti-inflammatory genes was markedly dysregulated in the intestinal mucosa of Glp1r À/À mice, and the abnormal gene expression profile was substantially reversed following selective reconstitution of GLP-1R+ intestinal IELs through bone marrow transplantation.…”

Discovery, characterization, and clinical development of the glucagon-like peptides

“…Understanding the mechanisms through which GLP-1 exerts cardioprotection is challenging, since the GLP-1R is largely expressed in atrial and not ventricular cardiomyocytes (81). Furthermore, the GLP-1R-dependent control of inflammation in heart and blood vessels is complex, as the predominant site of GLP-1R expression in the (murine) immune system is within the intestinal intraepithelial lymphocyte (82).…”

The Ascending GLP-1 Road From Clinical Safety to Reduction of Cardiovascular Complications

“…GLP-1R expression has been reported in immune cell populations such as macrophages, but rigorous demonstration of the presence of the canonical full-length GLP1R mRNA transcript or protein in tissue macrophages from animals or humans, including within diseased blood vessels, is lacking (3,51,52). The available evidence, from publicly available transcriptome analyses such as the ImmGen (Immunological Genome) Project or from experimental studies in mice, localizes functional immune cell GLP-1R expression to a subset of intestinal intraepithelial lymphocytes (53). Similar challenges relate to interpretation of reports linking GLP-1R signaling to inhibition of platelet aggregation and reduced thrombosis in mice (54); notably, it is not yet clear from extensive transcriptomic analyses whether the canonical GLP-1R is expressed, detectable, and functional in mature platelets.…”