Department of Medicine, Columbia University, New York, NY 10032, USA.
Cell Metab. 2010 Nov 3;12(5):467-82. doi: 10.1016/j.cmet.2010.09.010.
Macrophage apoptosis in advanced atheromata, a key process in plaque necrosis, involves the combination of ER stress with other proapoptotic stimuli. We show here that oxidized phospholipids, oxidized LDL, saturated fatty acids (SFAs), and lipoprotein(a) trigger apoptosis in ER-stressed macrophages through a mechanism requiring both CD36 and Toll-like receptor 2 (TLR2). In vivo, macrophage apoptosis was induced in SFA-fed, ER-stressed wild-type but not Cd36⁻(/)⁻ or Tlr2⁻(/)⁻ mice. For atherosclerosis, we combined TLR2 deficiency with that of TLR4, which can also promote apoptosis in ER-stressed macrophages. Advanced lesions of fat-fed Ldlr⁻(/)⁻ mice transplanted with Tlr4⁻(/)⁻Tlr2⁻(/)⁻ bone marrow were markedly protected from macrophage apoptosis and plaque necrosis compared with WT →Ldlr⁻(/)⁻ lesions. These findings provide insight into how atherogenic lipoproteins trigger macrophage apoptosis in the setting of ER stress and how TLR activation might promote macrophage apoptosis and plaque necrosis in advanced atherosclerosis.
晚期动脉粥样硬化中巨噬细胞凋亡是斑块坏死的关键过程，涉及内质网应激与其他促凋亡刺激的结合。我们在这里表明，氧化磷脂、氧化 LDL、饱和脂肪酸 (SFA) 和脂蛋白 (a) 通过一种需要 CD36 和 Toll 样受体 2 (TLR2) 的机制在 ER 应激的巨噬细胞中引发凋亡。在体内，SFA 喂养的内质网应激野生型小鼠中诱导了巨噬细胞凋亡，但 Cd36⁻(/)⁻或 Tlr2⁻(/)⁻小鼠中没有诱导。对于动脉粥样硬化，我们将 TLR2 缺陷与 TLR4 缺陷结合，TLR4 也可以促进 ER 应激的巨噬细胞凋亡。用 TLR4⁻(/)⁻Tlr2⁻(/)⁻骨髓移植的高脂肪喂养 Ldlr⁻(/)⁻小鼠的晚期病变与 WT →Ldlr⁻(/)⁻病变相比，明显免受巨噬细胞凋亡和斑块坏死的影响。这些发现提供了深入了解致动脉粥样硬化脂蛋白如何在 ER 应激的情况下引发巨噬细胞凋亡，以及 TLR 激活如何促进晚期动脉粥样硬化中的巨噬细胞凋亡和斑块坏死。
