Tacke Frank, Alvarez David, Kaplan Theodore J, Jakubzick Claudia, Spanbroek Rainer, Llodra Jaime, Garin Alexandre, Liu Jianhua, Mack Matthias, van Rooijen Nico, Lira Sergio A, Habenicht Andreas J, Randolph Gwendalyn J
Department of Gene and Cell Medicine, Mount Sinai School of Medicine, New York, New York 10029, USA.
J Clin Invest. 2007 Jan;117(1):185-94. doi: 10.1172/JCI28549.
Monocytes participate critically in atherosclerosis. There are 2 major subsets expressing different chemokine receptor patterns: CCR2(+)CX3CR1(+)Ly-6C(hi) and CCR2(-)CX3CR1(++)Ly-6C(lo) monocytes. Both C-C motif chemokine receptor 2 (CCR2) and C-X(3)-C motif chemokine receptor 1 (CX3CR1) are linked to progression of atherosclerotic plaques. Here, we analyzed mouse monocyte subsets in apoE-deficient mice and traced their differentiation and chemokine receptor usage as they accumulated within atherosclerotic plaques. Blood monocyte counts were elevated in apoE(-/-) mice and skewed toward an increased frequency of CCR2(+)Ly-6C(hi) monocytes in apoE(-/-) mice fed a high-fat diet. CCR2(+)Ly-6C(hi) monocytes efficiently accumulated in plaques, whereas CCR2(-)Ly-6C(lo) monocytes entered less frequently but were more prone to developing into plaque cells expressing the dendritic cell-associated marker CD11c, indicating that phagocyte heterogeneity in plaques is linked to distinct types of entering monocytes. CCR2(-) monocytes did not rely on CX3CR1 to enter plaques. Instead, they were partially dependent upon CCR5, which they selectively upregulated in apoE(-/-) mice. By comparison, CCR2(+)Ly-6C(hi) monocytes unexpectedly required CX3CR1 in addition to CCR2 and CCR5 to accumulate within plaques. In many other inflammatory settings, these monocytes utilize CCR2, but not CX3CR1, for trafficking. Thus, antagonizing CX3CR1 may be effective therapeutically in ameliorating CCR2(+) monocyte recruitment to plaques without impairing their CCR2-dependent responses to inflammation overall.
单核细胞在动脉粥样硬化过程中起着关键作用。有两个主要亚群，它们表达不同的趋化因子受体模式：CCR2(+)CX3CR1(+)Ly-6C(hi)单核细胞和CCR2(-)CX3CR1(++)Ly-6C(lo)单核细胞。C-C基序趋化因子受体2（CCR2）和C-X(3)-C基序趋化因子受体1（CX3CR1）均与动脉粥样硬化斑块的进展相关。在此，我们分析了载脂蛋白E缺陷小鼠中的小鼠单核细胞亚群，并追踪了它们在动脉粥样硬化斑块内积聚时的分化情况及趋化因子受体的使用情况。载脂蛋白E(-/-)小鼠血液中的单核细胞计数升高，且在喂食高脂饮食的载脂蛋白E(-/-)小鼠中，CCR2(+)Ly-6C(hi)单核细胞的频率偏向增加。CCR2(+)Ly-6C(hi)单核细胞有效地积聚在斑块中，而CCR2(-)Ly-6C(lo)单核细胞进入斑块的频率较低，但更倾向于发育成表达树突状细胞相关标志物CD11c的斑块细胞，这表明斑块中的吞噬细胞异质性与不同类型的进入单核细胞有关。CCR2(-)单核细胞进入斑块不依赖于CX3CR1。相反，它们部分依赖于CCR5，在载脂蛋白E(-/-)小鼠中它们会选择性地上调CCR5。相比之下，CCR2(+)Ly-6C(hi)单核细胞除了CCR2和CCR5外，意外地还需要CX3CR1才能在斑块内积聚。在许多其他炎症环境中，这些单核细胞利用CCR2而非CX3CR1进行迁移。因此，拮抗CX3CR1在治疗上可能有效地改善CCR2(+)单核细胞向斑块的募集，而不会损害它们对炎症的总体CCR2依赖性反应。
