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 ly6Chi monocytes 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 ly6Chi monocytes levels in MΦLRP1−/−→LDLR−/− and DKO→LDLR−/− mice, but it did not suppress ly6Chi 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.
- low density lipoprotein receptor-related protein-1
- tumor necrosis factor-alpha
- Received October 16, 2015.
- Accepted June 20, 2016.
- © 2016 American Heart Association, Inc.