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

ABSTRACT: Antiatherosclerotic effects of tumor necrosis factor-? (TNF-?) 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-? blockade in hyperlipidemic mice lacking either LRP1 (M?LRP1(-/-)) or apoE from macrophages.Lethally irradiated low-density lipoprotein receptor (LDLR)(-/-) mice were reconstituted with bone marrow from either wild-type, M?LRP1(-/-), apoE(-/-) or apoE(-/-)/M?LRP1(-/-)(DKO) mice, and then treated with the TNF-? inhibitor adalimumab while fed a Western-type diet. Adalimumab reduced plasma TNF-? 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-? and blood ly6C(hi) monocyte levels in M?LRP1(-/-)?LDLR(-/-) and DKO?LDLR(-/-) mice, but it did not suppress ly6C(hi) monocyte migration into the lesion or atherosclerosis progression.Our results show that TNF-? blockade exerts antiatherosclerotic effects that are dependent on the presence of macrophage LRP1.


PROVIDER: S-EPMC5346022 | BioStudies | 2016-01-01

REPOSITORIES: biostudies

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