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

ed for the analysis of DPP4 expression. Representative images (A) and histograms (B) showing the expression of DPP4 on CD36 + and CD36 − macrophages. C, Human MDMs were co-stained with CD36 and DPP4 and DPP4 expression on CD36 + or CD36 − MDMs are shown. atherosclerosis is complex. Depending on the cellular context and upstream pathways such as TLR4/3, TRIF could be proatherogenic or atheroprotective. Loss-of-function mutation of TRIF improved atherosclerosis in Ldlr −/− mice, while TLR3 deficiency in Ldlr −/− mice enhanced atherosclerosis development [49] . Since TRIF signaling is primarily induced by TLR3 and TLR4, these data suggest TLR4-mediated TRIF signaling promotes atherosclerosis, while the TLR3-dependent TRIF responses may be atheroprotective [49] . However, another study reported TLR3 and TLR4 signaling in bone marrow cells had proatherogenic effects in Ldlr −/− mice [50] . Studies by Ohnuma suggest that DPP4 may induce NFκB activation and monocyte maturation by interacting with caveolin-1 [4, 51, 52] . Therefore, up-regulation of DPP4 by oxLDL-induced innate signaling may in turn activate inflammatory signaling, resulting in a feed-forward loop. Stewart et al. previously reported that TLRs cooperate with CD36 to mediate oxLDL-induced inflammatory response [18] . CD36 is wellknown as a scavenger receptor responsible for oxLDL uptake and foam cell formation [53, 54] . We found in this study that CD36 is also involved in oxLDL-induced DPP4 up-regulation. Almost all DPP4 + cells also expressed CD36. Treatment of oxLDL increased the expression of CD36, which is consistent with previously reported findings [55] . In addition, deficiency of CD36 at least partially abolished oxLDL-induced DPP4 up-regulation. These findings suggest an important role for CD36 in oxLDL-induced DPP4 up-regulation.