SUN-737 Induction of the Pro-Diabetic Gene DPP4 by Glucocorticoids: New Evidence of Pro-Inflammatory Effects in Macrophages

Abstract

Glucocorticoids are potent endogenous anti-inflammatory molecules, with its receptor (GR) expressed in nearly all immune cells. Macrophages are heterogeneous cells having a central role in both tissue homeostasis and inflammation. Paradoxically glucocorticoids have a limited efficacy controlling these processes and inflammation resolution of macrophage-related diseases, such as type 2 diabetes, atherosclerosis and rheumatoid arthritis. To address this issue, we explored new glucocorticoid target genes in macrophages with potential clinical and therapeutic implications for these diseases. Analysis of genomic platforms identified the pro-diabetic exopeptidase dipeptidyl peptidase 4 (DPP4) as a novel glucocorticoid-responsive gene. GR directly induces its expression by binding to two glucocorticoid-responsive elements within the DPP4 promoter. Unexpectedly, DPP4 mediated the glucocorticoid-induced spontaneous macrophage migration. These actions were blocked by both GR and DPP4 siRNA knockdowns. Furthermore, two DPP4 inhibitors, Sitagliptin and Linagliptin, used clinically for the treatment of diabetes inhibited glucocorticoid-induced mobility of macrophages. DPP4 induction by glucocorticoids was also observed in murine peritoneal macrophages and pro-inflammatory M1 polarized macrophages and was associated with an increase in their migratory properties. Provocatively, DPP4 has been shown to be involved in the inflammatory macrophage profile associated with type 2 diabetes, obesity and atherosclerosis. Since macrophages require efficient cell movement for all their functions, such as sensing of Pattern Associated Molecular Patterns (PAMPs), phagocytosis and the antigen presentation, the DPP4 induction by glucocorticoids could potentiate the macrophage infiltration and their activation in chronic inflammatory tissues and diabetes.