TLR2 and neutrophils potentiate endothelial stress, apoptosis and detachment: implications for superficial erosion
TLR2 and neutrophils potentiate endothelial stress, apoptosis and detachment: implications for superficial erosion
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DOI：
10.1093/eurheartj/ehv044
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发表时间：
2015-06-07
影响因子：
39.3
通讯作者：
Libby, Peter
中科院分区：
文献类型：
--
作者：
Quillard, Thibaut;Araujo, Haniel Alves;Libby, Peter
目的动脉粥样硬化的表面性侵蚀可导致多种急性冠脉综合征，但发病机制不明。本研究验证了Toll样受体-2(TLR2)激活促进内皮细胞凋亡和剥蚀从而参与浅表糜烂发病机制的假说。方法与结果Toll样受体-2和中性粒细胞定位于人斑块表面侵蚀部位。在体外，TLR2配体(包括透明质酸，一种侵蚀病变中丰富的基质大分子)诱导内皮细胞应激，其特征是活性氧的产生、内质网(ER)的应激和细胞凋亡。中性粒细胞与内皮细胞(ECs)共同孵育可增强这些效应，并诱导EC凋亡和脱落。然后，我们根据与表面侵蚀、稳定的纤维病变或脆弱的病变相关的形态特征，对人类动脉粥样硬化斑块(n=56)进行了分类。人类动脉粥样硬化症的形态计量学分析定位于富含SMC的斑块中的中性粒细胞和中性粒细胞胞外陷阱(Net)附近的凋亡内皮细胞群。结论TLR2刺激和中性粒细胞参与的人动脉斑块的体外观察和分析表明，TLR2刺激和中性粒细胞参与可能使富含血管内皮细胞的斑块易发生浅层侵蚀和血栓并发症，从而导致内质网应激、细胞凋亡和血管内皮细胞的脱落。
Aims Superficial erosion of atheromata causes many acute coronary syndromes, but arises from unknown mechanisms. This study tested the hypothesis that Toll-like receptor-2 (TLR2) activation contributes to endothelial apoptosis and denudation and thus contributes to the pathogenesis of superficial erosion.Methods and results Toll-like receptor-2 and neutrophils localized at sites of superficially eroded human plaques. In vitro, TLR2 ligands (including hyaluronan, a matrixmacromolecule abundant in eroded lesions) induced endothelial stress, characterized by reactive oxygen species production, endoplasmic reticulum (ER) stress, and apoptosis. Co-incubation of neutrophils with endothelial cells (ECs) potentiated these effects and induced EC apoptosis and detachment. We then categorized human atherosclerotic plaques (n = 56) based on morphologic features associated with superficial erosion, 'stable' fibrotic, or 'vulnerable' lesions. Morphometric analyses of the human atheromata localized neutrophils and neutrophil extracellular traps (NETs) near clusters of apoptotic ECs in smooth muscle cell (SMC)-rich plaques. The number of luminal apoptotic ECs correlated with neutrophil accumulation, amount of NETs, and TLR2 staining in SMC-rich plaques, but not in 'vulnerable' atheromata.Conclusion These in vitro observations and analyses of human plaques indicate that TLR2 stimulation followed by neutrophil participation may render smooth muscle cell-rich plaques susceptible to superficial erosion and thrombotic complications by inducing ER stress, apoptosis, and favouring detachment of EC.