Abstract
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.
Original language | English (US) |
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Pages (from-to) | 1483-1495 |
Number of pages | 13 |
Journal | Arteriosclerosis, thrombosis, and vascular biology |
Volume | 36 |
Issue number | 8 |
DOIs | |
State | Published - Aug 1 2016 |
Keywords
- atherosclerosis
- inflammation
- low density lipoprotein receptor-related protein-1
- macrophages
- tumor necrosis factor-alpha
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine