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

Zhu L, Giunzioni I, Tavori H, Covarrubias R, Ding L, Zhang Y, Ormseth M, Major AS, Stafford JM, Linton MF, Fazio S
Arterioscler Thromb Vasc Biol. 2016 36 (8): 1483-95

PMID: 27365402 · PMCID: PMC5346022 · DOI:10.1161/ATVBAHA.116.307736

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.

© 2016 American Heart Association, Inc.

MeSH Terms (27)

Adalimumab Animals Anti-Inflammatory Agents Antigens, Ly Aorta Aortic Diseases Apolipoproteins E Apoptosis Atherosclerosis Bone Marrow Transplantation Cell Movement Diet, High-Fat Disease Models, Animal Drug Resistance Female Genetic Predisposition to Disease Macrophages Mice, Knockout Monocytes Necrosis Phenotype Plaque, Atherosclerotic Receptors, LDL Signal Transduction Tumor Necrosis Factor-alpha Tumor Suppressor Proteins Whole-Body Irradiation

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