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

In addition to its cell surface membrane-bound form, DPP4 also exists as a cleaved catalytically active extracellular domain circulating in plasma [7] . DPP4 is highly expressed on T cells, monocytes and antigen-presenting cells in adipose tissue and associated with T cellmediated inflammation [8, 9] . In addition, DPP4 is increased in obese patients with expression positively correlating to the degree of insulin resistance [8, 9] . Membrane bound DPP4 on hematopoietic and adipocytes may contribute to a substantial proportion of plasma DPP4 [9, 10] , implicating that DPP4 on these cell types acts as an important regulator of incretin action. Studies by our team and other groups have suggested an important role for immune cell-expressing DPP4 in diabetes and cardiovascular disease [8, [11] [12] [13] . However, the mechanisms and mediators of DPP4 expression on these cells are poorly understood. Given the central role of monocyte/macrophage in atherosclerosis, we recently reported that the expression of DPP4 on monocytes and plasma DPP4 activity were increased in patients with atherosclerosis and positively correlated with atherosclerotic plaque volume [14] . In addition, the DPP4 expression level on monocytes was also associated with plasma levels of non-HDL cholesterol and triglycerides [14] . However, the mechanisms by which DPP4 is up-regulated in cardiometabolic disease remain elucidated. In this study, we found that treatment of oxidized low-density lipoprotein (oxLDL), but not native LDL, elevated DPP4 expression on macrophages, which was attenuated by the inhibition of Toll-like receptor 4 (TLR4) or downstream Toll/IL-1R domaincontaining adaptor-inducing IFN-β (TRIF). DPP4 expression almost exclusively occurred on CD36 + monocytes and CD36 deficient macrophages showed an attenuated up-regulation of DPP4 in response to oxLDL. For the first time to our knowledge, these findings demonstrated an important role for oxidized lipids in immune cell DPP4 regulation and may provide an integrated mechanism linking abnormal postprandial glucose metabolism with oxidized lipids and inflammation.