Loss of Macrophage Low-Density Lipoprotein Receptor-Related Protein 1 Confers Resistance to the Antiatherogenic Effects of Tumor Necrosis Factor-α Inhibition

Objective - Antiatherosclerotic effects of tumor necrosis factor-α (TNF-α) blockade in patients with systemic inflammatory states are not conclusively demonstrated, which suggests that effects depend on the cause of inflammation. Macrophage LRP1 (low-density lipoprotein receptor-related protein 1) and apoE contribute to inflammation through different pathways. We studied the antiatherosclerosis effects of TNF-α blockade in hyperlipidemic mice lacking either LRP1 (MΦLRP1 ^-/-) or apoE from macrophages. Approach and Results - Lethally irradiated low-density lipoprotein receptor (LDLR) ^-/- mice were reconstituted with bone marrow from either wild-type, MΦLRP1 ^-/-, apoE ^-/- or apoE ^-/- /MΦLRP1 ^-/- (DKO) mice, and then treated with the TNF-α inhibitor adalimumab while fed a Western-type diet. Adalimumab reduced plasma TNF-α concentration, suppressed blood ly6C hi monocyte levels and their migration into the lesion, and reduced lesion cellularity and inflammation in both wild-type→LDLR ^-/- and apoE ^-/- →LDLR ^-/- mice. Overall, adalimumab reduced lesion burden by 52% to 57% in these mice. Adalimumab reduced TNF-α and blood ly6C hi monocyte levels in MΦLRP1 ^-/- →LDLR ^-/- and DKO→LDLR ^-/- mice, but it did not suppress ly6C hi monocyte migration into the lesion or atherosclerosis progression. Conclusions - Our results show that TNF-α blockade exerts antiatherosclerotic effects that are dependent on the presence of macrophage LRP1.