Hyperlipidemia-Triggered Neutrophilia Promotes Early Atherosclerosis
Hyperlipidemia-Triggered Neutrophilia Promotes Early Atherosclerosis
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DOI：
10.1161/circulationaha.110.961714
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发表时间：
2010-11-02
期刊：
影响因子：
37.8
通讯作者：
Soehnlein, Oliver
中科院分区：
文献类型：
--
作者：
Drechsler, Maik;Megens, Remco T. A.;Soehnlein, Oliver
背景-炎症和免疫细胞的激活是动脉粥样硬化发展的关键机制。先前的数据表明单核细胞和T淋巴细胞在病变形成中的重要作用，而中性粒细胞的贡献仍有待确定。在这里，我们调查外周血中性粒细胞计数，中性粒细胞招聘动脉粥样硬化病变的影响，和中性粒细胞在动脉粥样硬化病变形成Apoe（-/-）mice.Methods和Results-Hypocholesterolemia诱导嗜中性粒细胞，这是由于增强粒细胞生成和增强动员骨髓的重要性。高胆固醇血症诱发的嗜脂血症的程度与早期动脉粥样硬化病变形成的程度呈正相关。反过来，血小板减少的小鼠在动脉粥样硬化病变形成的早期而不是晚期显示斑块大小减少。酶消化的血小板的流式细胞术进一步显示了血小板减少小鼠中细胞斑块组成的改变，炎性单核细胞和巨噬细胞的数量减少。主动脉嗜中性粒细胞浸润在高脂饮食开始后4周达到峰值，之后减少。研究发现，中性粒细胞向大动脉的募集取决于CCR 1、CCR 2、CCR 5和CXCR 2，这与外周静脉募集形成鲜明对比，外周静脉募集仅需要CCR 2和CXCR 2。CCR 1和CCR 5的参与对应于血小板衍生的趋化因子CCL 5在动脉中的内皮沉积，而不是在vein. Conclusions，我们的数据提供的证据表明，高胆固醇血症诱导的嗜中性粒细胞是多因素的，主要是在动脉粥样硬化的早期阶段，中性粒细胞浸润动脉。总的来说，这些数据表明中性粒细胞在动脉粥样硬化的发生中起重要作用。（循环。2010;122：1837-1845）。
Background-Inflammation and activation of immune cells are key mechanisms in the development of atherosclerosis. Previous data indicate important roles for monocytes and T lymphocytes in lesion formation, whereas the contribution of neutrophils remains to be firmly established. Here, we investigate the effect of hypercholesterolemia on peripheral neutrophil counts, neutrophil recruitment to atherosclerotic lesions, and the importance of neutrophils in atherosclerotic lesion formation in Apoe(-/-) mice.Methods and Results-Hypercholesterolemia induces neutrophilia, which was attributable to enhanced granulopoiesis and enhanced mobilization from the bone marrow. The degree of hypercholesterolemia-induced neutrophilia was positively correlated with the extent of early atherosclerotic lesion formation. In turn, neutropenic mice display reduced plaque sizes at early but not late stages of atherosclerotic lesion formation. Flow cytometry of enzymatically digested aortas further shows altered cellular plaque composition in neutropenic mice with reduced numbers of inflammatory monocytes and macrophages. Aortic neutrophil infiltration peaks 4 weeks after the start of a high-fat diet and decreases afterward. The recruitment of neutrophils to large arteries was found to depend on CCR1, CCR2, CCR5, and CXCR2, which contrasts to peripheral venous recruitment, which requires CCR2 and CXCR2 only. The involvement of CCR1 and CCR5 corresponded to the endothelial deposition of the platelet-derived chemokine CCL5 in arteries but not in veins.Conclusions-Our data provide evidence that hypercholesterolemia-induced neutrophilia is multifactorial and that neutrophils infiltrate arteries primarily during early stages of atherosclerosis. Collectively, these data suggest an important role of neutrophils in the initiation of atherosclerosis. (Circulation. 2010;122:1837-1845.)