Lin Zhu1, Ilaria Giunzioni1, Hagai Tavori1, Roman Covarrubias1, Lei Ding1, Youmin Zhang1, Michelle Ormseth1, Amy S Major1, John M Stafford1, MacRae F Linton1, Sergio Fazio2. 1. From the Division of Cardiovascular Medicine (L.Z., R.C., L.D., Y.Z., A.S.M., M.F.L.), Division of Diabetes, Endocrinology, and Metabolism (L.Z., J.M.S.), Division of Rheumatology, Department of Medicine (M.O.), Vanderbilt University Medical Center, Nashville, TN; Tennessee Valley Healthcare System, Nashville (L.Z., J.M.S.); and Center for Preventive Cardiology, Knight Cardiovascular Institute, Oregon Health & Science University, Portland (I.G., H.T., S.F.). 2. From the Division of Cardiovascular Medicine (L.Z., R.C., L.D., Y.Z., A.S.M., M.F.L.), Division of Diabetes, Endocrinology, and Metabolism (L.Z., J.M.S.), Division of Rheumatology, Department of Medicine (M.O.), Vanderbilt University Medical Center, Nashville, TN; Tennessee Valley Healthcare System, Nashville (L.Z., J.M.S.); and Center for Preventive Cardiology, Knight Cardiovascular Institute, Oregon Health & Science University, Portland (I.G., H.T., S.F.). fazio@ohsu.edu.
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.
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.
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