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

Lin Zhu, Ilaria Giunzioni, Hagai Tavori, Roman Covarrubias, Lei Ding, Youmin Zhang, Michelle Ormseth, Amy S. Major, John M. Stafford, Mac Rae F Linton, Sergio Fazio

    Research output: Contribution to journalArticle

    18 Scopus citations

    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 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 ly6C monocytes levels in MΦLRP1→LDLR and DKO→LDLR mice, but it did not suppress ly6C 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 languageEnglish (US)
    JournalArteriosclerosis, Thrombosis, and Vascular Biology
    DOIs
    StateAccepted/In press - Jun 30 2016

    ASJC Scopus subject areas

    • Cardiology and Cardiovascular Medicine

    Fingerprint Dive into the research topics of 'Loss of Macrophage Low-Density Lipoprotein Receptor–Related Protein 1 Confers Resistance to the Antiatherogenic Effects of Tumor Necrosis Factor-α Inhibition'. Together they form a unique fingerprint.

  • Cite this