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

Experimental studies have strongly demonstrated a role for DPP4 in the progression of atherosclerosis with an increased expression in proinflammatory monocytes/macrophages in plaque [12] . However, given the relative neutrality of recent trials with DPP4 catalytic inhibitors [21, 22] , the role of DPP4 has been questioned. One potential reason for the lack of efficacy in these studies may relate to a divergent role/ function of the catalytic versus non-catalytic function of DPP4 particularly in cell types such as monocytes and T cells. Thus our investigation was focused on the expression of membrane bound DPP4 in atherosclerosis. We have previously shown that DPP4 on macrophages and dendritic cells may enhance adipose tissue inflammation via non-catalytic pathways [8] . A recent study by Ghorpade et al. also reported that DPP4 acts with plasma factor Xa to inflame adipose tissue macrophage. Silencing expression of DPP4 in hepatocytes, but not enzymatic inhibition of DPP4 by sitagliptin, reduced adipose tissue inflammation and insulin resistance [23] . In the current study, we observed that catalytic inhibition of DPP4 increased the expression of DPP4 on macrophages. These results indicate that the compensatory upregulation of DPP4 by DPP4 catalytic inhibition may promote inflammation, which could be a possible explanation for the neutral effects of DPP4 inhibitors on cardiovascular outcome.