Montecucco F, Braunersreuther V, Burger F, Lenglet S, Pelli G, Carbone F, Fraga-Silva R, Stergiopulos N, Monaco C, Mueller C, Pagano S, Dallegri F, Mach F, Vuilleumier N
Fabrizio Montecucco, MD, PhD, Avenue de la Roseraie 64, Division of Laboratory Medicine and Department of Genetics and Laboratory Medicine, Geneva University Hospitals, 4 rue Gabrielle-Perret-Gentil, 1205 Geneva, Switzerland, Tel.: +41 22 38 27 238, Fax: +41 22 38 27 245, E mail:
Thromb Haemost. 2015 Aug;114(2):410-22. doi: 10.1160/TH14-12-1039. Epub 2015 Apr 16.
Auto-antibodies to apolipoprotein A-1 (anti-apoA-1 IgG) were shown to promote inflammation and atherogenesis, possibly through innate immune receptors signalling. Here, we aimed at investigating the role of Toll-like receptors (TLR) 2 and 4 on anti-apoA-1 IgG-induced atherosclerotic plaque vulnerability, myocardial necrosis and mortality in mice. Adult male apolipoprotein E knockout (ApoE)-/- (n=72), TLR2-/-ApoE-/- (n=36) and TLR4-/-Apo-/- (n=28) mice were intravenously injected with 50 µg/mouse of endotoxin-free polyclonal anti-apoA-1 IgG or control isotype IgG (CTL IgG) every two weeks for 16 weeks. Atherosclerotic plaque size and vulnerability were assessed by histology. Myocardial ischaemia and necrosis, respectively, were determined by electrocardiographic (ECG) changes assessed by telemetry and serum troponin I (cTnI) measurements. Impact on survival was assessed by Kaplan-Meier analyses. In ApoE-/- mice, anti-apoA-1 IgG passive immunisation enhanced histological features of atherosclerotic plaque vulnerability (increase in neutrophil and MMP-9 and reduction in collagen content), induced a substantial cTnI elevation (p=0.001), and increased mortality rate by 23 % (LogRank, p=0.04) when compared to CTL IgG. On a subgroup of ApoE-/- mice equipped with telemetry (n=4), a significant ST-segment depression was noted in anti-apoA-1 IgG-treated mice when compared to CTL IgG recipients (p< 0.001), and an acute ST-segment elevation myocardial infarction preceding mouse death was observed in one case. The deleterious effects of anti-apoA-1 IgG on atherosclerotic plaque vulnerability, myocardial necrosis and death were partially reversed in TLR2-/-ApoE-/- and TLR4-/-ApoE-/- backgrounds. In conclusion, anti-apoA-1 auto-antibodies seem to be active mediators of atherosclerotic plaque vulnerability, myocardial necrosis, and mortality in mice through TLR2- and TLR4-mediated pathways.
载脂蛋白A-1自身抗体（抗载脂蛋白A-1 IgG）被证明可促进炎症和动脉粥样硬化的发生，可能是通过天然免疫受体信号传导。在此，我们旨在研究Toll样受体（TLR）2和4在抗载脂蛋白A-1 IgG诱导的小鼠动脉粥样硬化斑块易损性、心肌坏死和死亡率中的作用。成年雄性载脂蛋白E基因敲除（ApoE）-/-小鼠（n = 72）、TLR2-/-ApoE-/-小鼠（n = 36）和TLR4-/-ApoE-/-小鼠（n = 28），每两周静脉注射50 μg/小鼠无内毒素的多克隆抗载脂蛋白A-1 IgG或对照同种型IgG（CTL IgG），共16周。通过组织学评估动脉粥样硬化斑块大小和易损性。分别通过遥测评估的心电图（ECG）变化和血清肌钙蛋白I（cTnI）测量来确定心肌缺血和坏死。通过Kaplan-Meier分析评估对生存的影响。在ApoE-/-小鼠中，与CTL IgG相比，抗载脂蛋白A-1 IgG被动免疫增强了动脉粥样硬化斑块易损性的组织学特征（中性粒细胞和MMP-9增加，胶原蛋白含量减少），导致cTnI显著升高（p = 0.001），死亡率增加23%（LogRank，p = 0.04）。在配备遥测的ApoE-/-小鼠亚组（n = 4）中，与接受CTL IgG的小鼠相比，抗载脂蛋白A-1 IgG处理的小鼠出现显著的ST段压低（p < 0.001），并且在一例中观察到小鼠死亡前出现急性ST段抬高型心肌梗死。在TLR2-/-ApoE-/-和TLR4-/-ApoE-/-背景下，抗载脂蛋白A-1 IgG对动脉粥样硬化斑块易损性、心肌坏死和死亡的有害作用部分得到逆转。总之，抗载脂蛋白A-1自身抗体似乎是通过TLR2和TLR4介导的途径，在小鼠动脉粥样硬化斑块易损性、心肌坏死和死亡率中发挥作用的活性介质。
