Atherogenic lipids and lipoproteins trigger CD36-TLR2-dependent apoptosis in macrophages undergoing endoplasmic reticulum stress.
Atherogenic lipids and lipoproteins trigger CD36-TLR2-dependent apoptosis in macrophages undergoing endoplasmic reticulum stress.
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DOI：
10.1016/j.cmet.2010.09.010
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发表时间：
2010-11-03
期刊：
影响因子：
29
通讯作者：
Tabas I
中科院分区：
文献类型：
--
作者：
Seimon TA;Nadolski MJ;Liao X;Magallon J;Nguyen M;Feric NT;Koschinsky ML;Harkewicz R;Witztum JL;Tsimikas S;Golenbock D;Moore KJ;Tabas I
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）的机制触发内质网应激巨噬细胞的凋亡。在体内，sfa喂养、er应激的野生型小鼠可诱导巨噬细胞凋亡，而Cd36−/−或Tlr2−/−小鼠则不能。对于动脉粥样硬化，我们将TLR2缺陷与TLR4缺陷结合起来，它们也可以促进er应激巨噬细胞的凋亡。与WT→Ldlr−/−病变相比，移植Tlr4−/−Tlr2−/−骨髓的脂肪喂养Ldlr−/−小鼠晚期病变可明显保护巨噬细胞凋亡和斑块坏死。这些发现揭示了粥样硬化脂蛋白如何在内质网应激下触发巨噬细胞凋亡，以及TLR激活如何促进晚期动脉粥样硬化中巨噬细胞凋亡和斑块坏死。
Macrophage apoptosis in advanced atheromata, a key process in plaque necrosis, involves the combination of ER stress with other pro-apoptotic 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.
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影响因子：
120.7
作者：
Erqou, Sebhat;Kaptoge, Stephen;Perry, Philip L.;Di Angelantonio, Emanuele;Thompson, Alexander;White, Ian R.;Marcovina, Santica M.;Collins, Rory;Thompson, Simon G.;Danesh, John
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影响因子：
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Hotamisligil, Goekhan S.
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通讯作者：
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影响因子：
6.5
作者：
Bergmark, Claes;Dewan, Asheesh;Tsimikas, Sotirios
通讯作者：
Tsimikas, Sotirios
影响因子：
4.4
作者：
Dewas, C;Fay, M;El-Benna, J
通讯作者：
El-Benna, J