Combined inhibition of CCL2, CX3CR1, and CCR5 abrogates Ly6Chi and Ly6Clo monocytosis and almost abolishes atherosclerosis in hypercholesterolemic mice
Combined inhibition of CCL2, CX3CR1, and CCR5 abrogates Ly6Chi and Ly6Clo monocytosis and almost abolishes atherosclerosis in hypercholesterolemic mice
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DOI：
10.1161/circulationaha.107.745091
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发表时间：
2008-04-01
期刊：
影响因子：
37.8
通讯作者：
Mallat, Ziad
中科院分区：
文献类型：
--
作者：
Combadiere, Christophe;Potteaux, Stephane;Mallat, Ziad
背景-单核细胞是动脉粥样硬化形成的关键介质。单个趋化因子或趋化因子受体的缺失会导致病变发展的显着但仅部分抑制，而CXCL16或CCR1等其他信号的缺乏会加速动脉粥样硬化。仍然缺乏特定趋化因子途径可能协同促进单核细胞积聚到发炎组织（特别是动脉粥样硬化动脉）的证据。方法和结果 - 在这里，我们表明，在非炎症和动脉粥样硬化条件下，趋化因子介导的信号关键决定血液和骨髓中单核细胞的频率。特别是，CCL2-、CX3CR1-和CCR5依赖性信号差异性地改变CD11b(+) Ly6G(-) 7/4(hi)（也称为Ly6C(hi)）和CD11b(+) Ly6G(-) 7/4(lo) (Ly6C(lo))单核细胞作用。在高胆固醇血症、动脉粥样硬化易感性载脂蛋白 E 缺陷小鼠中，联合抑制 CCL2、CX3CR1 和 CCR5 会导致骨髓单核细胞增多，尽管存在持续性高胆固醇血症，但循环单核细胞会进一步减少。这些效果与动脉粥样硬化显着且累加地减少 90% 相关。有趣的是，病变大小与循环单核细胞的数量高度相关，特别是 CD11b(+) Ly6G(-) 7/4(lo) 子集。结论 - CCL2、CX3CR1 和 CCR5 在动脉粥样硬化形成中发挥独立和相加的作用。通过这些途径介导的信号关键决定了循环单核细胞亚群的频率，从而解释了几乎所有巨噬细胞积聚到动脉粥样硬化的动脉中。
Background - Monocytes are critical mediators of atherogenesis. Deletion of individual chemokines or chemokine receptors leads to significant but only partial inhibition of lesion development, whereas deficiency in other signals such as CXCL16 or CCR1 accelerates atherosclerosis. Evidence that particular chemokine pathways may cooperate to promote monocyte accumulation into inflamed tissues, particularly atherosclerotic arteries, is still lacking.Methods and Results - Here, we show that chemokine-mediated signals critically determine the frequency of monocytes in the blood and bone marrow under both noninflammatory and atherosclerotic conditions. Particularly, CCL2-, CX3CR1-, and CCR5-dependent signals differentially alter CD11b(+) Ly6G(-) 7/4(hi) ( also known as Ly6C(hi)) and CD11b(+) Ly6G(-) 7/4(lo) ( Ly6C(lo)) monocytosis. Combined inhibition of CCL2, CX3CR1, and CCR5 in hypercholesterolemic, atherosclerosis-susceptible apolipoprotein E-deficient mice leads to abrogation of bone marrow monocytosis and to additive reduction in circulating monocytes despite persistent hypercholesterolemia. These effects are associated with a marked and additive 90% reduction in atherosclerosis. Interestingly, lesion size highly correlates with the number of circulating monocytes, particularly the CD11b(+) Ly6G(-) 7/4(lo) subset.Conclusions - CCL2, CX3CR1, and CCR5 play independent and additive roles in atherogenesis. Signals mediated through these pathways critically determine the frequency of circulating monocyte subsets and thereby account for almost all macrophage accumulation into atherosclerotic arteries.