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

Given that oxidatively modified cholesterol is fundamental to the pathogenesis of atherosclerosis and is widely believed to represent a plausible mechanism of accelerated atherosclerosis in insulin resistance/type 2 diabetes, we tested the effect of LDL (native or oxidized) on the regulation of DPP4 expression. After 24-h treatment with 25 Fig. 2b ). Dose response experiments revealed that oxLDL dose-dependently enhanced DPP4 expression on macrophages (Supplemental Fig. 1 ). Similar findings were observed in peritoneal macrophages from C57BL/6 mice (Fig. 2c) . Furthermore, the upregulation of DPP4 following oxLDL treatment was accompanied by an increased expression of inflammatory cytokine IL-1β (Fig. 2d) . There was also a trend of increase in the expressions of NLRP3 and Caspase-1, two important components of NLRP3 inflammasome complex which is responsible for the maturation of IL-1β (Fig. 2d) . To further confirm this result in humans, we prepared monocyte-derived macrophages (MDMs) from human peripheral blood monocytes and treated these cells with oxLDL. oxLDL increased DPP4 expression on human macrophages by nearly two fold (Fig. 2e) . We next examined if 27-hydroxycholesterol (27OH-Ch), an oxidized cholesterol and important component of oxLDL, could induce DPP4 upregulation. Interestingly, DPP4 was not significantly upregulated after 27OH-Ch treatment, suggesting that the upregulation of DPP4 may not be mediated by free form of oxidized cholesterol (Supplemental Fig. 2 ).