Oxidized LDL upregulates macrophage DPP4 expression via TLR4/TRIF/CD36 pathways

Rao, Xiaoquan; Zhao, Shi; Braunstein, Zachary; Mao, Hong; Razavi, Michael; Duan, Lihua; Wei, Yingying; Toomey, Amelia C.; Rajagopalan, Sanjay; Zhong, Jixin

DPP4, an important regulator of the incretin-insulin axis, is expressed by a number of immune cells [2] . While the role of global DPP4 in diabetes and cardiovascular disease has been well studied, the function of immune cell-derived DPP4 in cardiometabolic disease remains elucidated. To determine the role of immune cell-expressing DPP4 in cardiovascular disease, we first examined the expression of DPP4 on circulating immune cells using Flowsight® imaging flow cytometry. Results indicate that monocytes and T cells are the major populations expressing DPP4 in the human peripheral blood, while the majority of granulocytes and B cells did not express DPP4 (Fig. 1a ). In addition to membrane-bound DPP4, DPP4 can also be cleaved from the cell membrane and present as a soluble form in the plasma [2] . We next detected the enzymatic activity of membrane-bound DPP4 on the white blood cells and soluble DPP4 in the plasma. As a result, leukocytes contributed considerably to the enzymatic activity of DPP4 in the circulation (Figs. 1b & 1c) . To examine if immune cells also contribute to the generation of soluble DPP4 in the plasma, DPP4 knockout mice were irradiated and transplanted with wild-type (WT) or DPP4 −/− bone marrow. Plasma was isolated for the detection of DPP4 activity after 12 weeks. As depicted in Fig. 1d , mice with WT bone marrow showed a significantly higher level of plasma DPP4 activity compared to those with DPP4 −/− bone marrow, suggesting that immune cells contribute to the generation of soluble DPP4. In addition, enzymatic inhibition of DPP4 inhibitor (DPP4i) for 4 weeks increased the expression of DPP4 on macrophages (Figs. 1e & 1f) , suggesting that there may be a negative feedback loop to control DPP4 expression and enzymatic activity.