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

    17 Citations (Scopus)

    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

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    LDL Lipoproteins
    Tumor Necrosis Factor-alpha
    Macrophages
    Apolipoproteins E
    Proteins
    Monocytes
    Inflammation
    LDL Receptors
    Atherosclerosis
    Bone Marrow
    Adalimumab

    ASJC Scopus subject areas

    • Cardiology and Cardiovascular Medicine

    Cite this

    Loss of Macrophage Low-Density Lipoprotein Receptor–Related Protein 1 Confers Resistance to the Antiatherogenic Effects of Tumor Necrosis Factor-α Inhibition. / Zhu, Lin; Giunzioni, Ilaria; Tavori, Hagai; Covarrubias, Roman; Ding, Lei; Zhang, Youmin; Ormseth, Michelle; Major, Amy S.; Stafford, John M.; Linton, Mac Rae F; Fazio, Sergio.

    In: Arteriosclerosis, Thrombosis, and Vascular Biology, 30.06.2016.

    Research output: Contribution to journalArticle

    Zhu, Lin ; Giunzioni, Ilaria ; Tavori, Hagai ; Covarrubias, Roman ; Ding, Lei ; Zhang, Youmin ; Ormseth, Michelle ; Major, Amy S. ; Stafford, John M. ; Linton, Mac Rae F ; Fazio, Sergio. / Loss of Macrophage Low-Density Lipoprotein Receptor–Related Protein 1 Confers Resistance to the Antiatherogenic Effects of Tumor Necrosis Factor-α Inhibition. In: Arteriosclerosis, Thrombosis, and Vascular Biology. 2016.
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    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.",
    author = "Lin Zhu and Ilaria Giunzioni and Hagai Tavori and Roman Covarrubias and Lei Ding and Youmin Zhang and Michelle Ormseth and Major, {Amy S.} and Stafford, {John M.} and Linton, {Mac Rae F} and Sergio Fazio",
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    T1 - Loss of Macrophage Low-Density Lipoprotein Receptor–Related Protein 1 Confers Resistance to the Antiatherogenic Effects of Tumor Necrosis Factor-α Inhibition

    AU - Zhu, Lin

    AU - Giunzioni, Ilaria

    AU - Tavori, Hagai

    AU - Covarrubias, Roman

    AU - Ding, Lei

    AU - Zhang, Youmin

    AU - Ormseth, Michelle

    AU - Major, Amy S.

    AU - Stafford, John M.

    AU - Linton, Mac Rae F

    AU - Fazio, Sergio

    PY - 2016/6/30

    Y1 - 2016/6/30

    N2 - 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.

    AB - 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.

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    SN - 1079-5642

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