Objective:
Dipeptidyl peptidase-4 (DPP4) is well known for its ability to modulate post-prandial blood glucose by inactivation of incretin hormones. DPP4 is highly expressed on innate and adaptive immune cell populations and is recognized to be regulated upon inflammatory activation. We investigated the role of myeloid DPP4 in post-prandial glucose regulation and a role for TLR4-MyD88 in humans and mice.
Methods and Results:
We evaluated DPP4 expression on circulating immune cells in patients with atherosclerosis (ATH, n=20) and compared them with healthy controls without atherosclerosis using flow cytometry. ATH patients had increased DPP4 expression on peripheral blood monocytes (4.22 ± 0.44 vs. 5.76 ± 0.44, in control vs. ATH, p=0.037) as well as CD4+ T cells (27.46 ± 2.67 vs. 48.06 ± 1.96, control vs. ATH, p<0.0001). More importantly, DPP4 expression on T cells and monocytes correlated with plasma non HDL-Cholesterol level (R2=0.153, p=0.036 and R2=0.244, 0.012 respectively). Stimulation with LPS increased DPP4 expression on human peripheral blood monocytes by ~4-fold. DPP4 up-regulation by LPS was abrogated by Toll-like receptor-4 (TLR4) knockdown using siRNA. Bone marrow monocytes deficient for MyD88, an adaptor protein for TLR signaling, displayed reduced expression of DPP4. Consistent with these findings, MyD88-/- mice also showed improved post-prandial glycemia in response to oral glucose challenge, a phenotype seen in DPP4-/- mice.
Conclusions:
Our results suggest a previously unrecognized role for TLR4-MyD88 as a critical regulator of DPP4 expression and post-prandial glucose control.
NF-kappa B Activation in Peripheral Blood Monocytes/Macrophages and T Cells during Acute Kawasaki Disease