Protective role of CXC receptor 4/CXC ligand 12 unveils the importance of neutrophils in atherosclerosis
Protective role of CXC receptor 4/CXC ligand 12 unveils the importance of neutrophils in atherosclerosis
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DOI：
10.1161/circresaha.107.160697
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发表时间：
2008-02-01
影响因子：
20.1
通讯作者：
Weber, Christian
中科院分区：
文献类型：
--
作者：
Zernecke, Alma;Bot, Ilze;Weber, Christian
CXC配体（CXCL）12/CXC受体（CXCR）4趋化因子-受体轴控制造血、器官发育和血管生成，但其在动脉粥样硬化的炎症发病机制中的作用尚不清楚。在此，我们发现，在载脂蛋白E缺陷（Apoe（-/-））或低密度脂蛋白受体缺陷（Ldlr（-/-））小鼠中，通过小分子拮抗剂、遗传性Cxcr 4缺陷或骨髓嵌合体中Cxcr 4降解因子的慢病毒转导干扰Cxcl 12/Cxcr 4可加重饮食诱导的动脉粥样硬化。Cxcr 4的慢性阻断引起白细胞增多和中性粒细胞的扩张，并增加斑块中的中性粒细胞含量，与细胞凋亡和促炎表型相关。尽管循环中性粒细胞被招募到动脉粥样硬化病变，但中性粒细胞的耗竭减少了斑块形成，并在阻断Cxcr 4后防止其恶化。因此，破坏Cxcl 12/Cxcr 4通过扰乱中性粒细胞稳态促进病变形成，表明Cxcl 12/Cxcr 4控制中性粒细胞对小鼠动脉粥样硬化形成的重要贡献。
The CXC ligand (CXCL) 12/CXC receptor (CXCR) 4 chemokine-receptor axis controls hematopoiesis, organ development, and angiogenesis, but its role in the inflammatory pathogenesis of atherosclerosis is unknown. Here we show that interference with Cxcl12/Cxcr4 by a small-molecule antagonist, genetic Cxcr4 deficiency, or lentiviral transduction with Cxcr4 degrakine in bone marrow chimeras aggravated diet-induced atherosclerosis in apolipoprotein E-deficient (Apoe(-/-)) or LDL receptor-deficient (Ldlr(-/-)) mice. Chronic blockade of Cxcr4 caused leukocytosis and an expansion of neutrophils and increased neutrophil content in plaques, associated with apoptosis and a proinflammatory phenotype. Whereas circulating neutrophils were recruited to atherosclerotic lesions, depletion of neutrophils reduced plaque formation and prevented its exacerbation after blocking Cxcr4. Disrupting Cxcl12/Cxcr4 thus promotes lesion formation through deranged neutrophil homeostasis, indicating that Cxcl12/Cxcr4 controls the important contribution of neutrophils to atherogenesis in mice.