CCR6 selectively promotes monocyte mediated inflammation and atherogenesis in mice
CCR6 selectively promotes monocyte mediated inflammation and atherogenesis in mice
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DOI：
10.1160/th13-01-0017
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发表时间：
2013-12-01
影响因子：
6.7
通讯作者：
Zernecke, Alma
中科院分区：
文献类型：
--
作者：
Manthey, Helga D.;Cochain, Clement;Zernecke, Alma
趋化因子受体 CCR6 由参与动脉粥样硬化形成的各种细胞亚群表达，例如单核细胞、Th17 和调节性 T 细胞。为了进一步明确CCR6在动脉粥样硬化中的作用，将CCR6缺陷型(Ccr6(-1-))小鼠与低密度脂蛋白受体缺陷型(Ldlrl(-/-))小鼠杂交，产生CCR6缺陷型易发生动脉粥样硬化的小鼠。与Ldl(-/-)对照组相比，高脂饮食喂养的Ccr6(-1-)Ldlr(-/-)小鼠主动脉窦和主动脉的动脉粥样硬化负担减少，这与病变巨噬细胞积聚的严重抑制有关。 T 细胞的局部和全身分布，包括 Th1、Th17 和调节性 T 细胞的频率没有改变。相比之下，Ccr6(-1-)Ldrlr(-/-)小鼠中Gr-1（高）和Gr1（低）单核细胞的循环计数均减少。此外，CCR6 在体外可促进单核细胞与发炎内皮的粘附，在体内可促进白细胞与颈动脉的粘附。最后，在急性炎症气囊模型中，CCR6 选择性地募集单核细胞而不是 T 细胞。我们在这里表明，CCR6 在多个水平上发挥作用，调节单核细胞/巨噬细胞向发炎血管的动员、粘附和募集，从而促进动脉粥样硬化，但对于高胆固醇血症相关的适应性免疫启动来说是可有可无的。因此，靶向 CCR6 或其配体 CCL20 可能是缓解动脉粥样硬化的一种有前途的治疗策略。
The chemokine receptor CCR6 is expressed by various cell subsets implicated in atherogenesis, such as monocytes, Th17 and regulatory T cells. In order to further define the role of CCR6 in atherosclerosis, CCR6-deficient (Ccr6(-1-)) mice were crossed with low-density lipoprotein receptor-deficient (Ldlrl(-/-)) mice to generate atherosclerosis-prone mice deficient in CCR6. Compared to Ldl(-/-) controls, atherosclerotic burden in the aortic sinus and aorta were reduced in Ccr6(-1-)Ldlr(-/-) mice fed a high fat diet, associated with a profound depression in lesional macrophage accumulation. Local and systemic distributions of T cells, including frequencies of Th1, Th17 and regulatory T cells were unaltered. In contrast, circulating counts of both Gr-1(high) and Gr1(low) monocytes were reduced in Ccr6(-1-)Ldrlr(-/-) mice. Moreover, CCR6 was revealed to promote monocyte adhesion to inflamed endothelium in vitro and leukocyte adhesion to carotid arteries in vivo. Finally, CCR6 selectively recruited monocytes but not T cells in an acute inflammatory air pouch model. We here show that CCR6 functions on multiple levels and regulates the mobilisation, adhesion and recruitment of monocytes/macrophages to the inflamed vessel, thereby promoting atherosclerosis, but is dispensable for hypercholesterolaemia-associated adaptive immune priming. Targeting CCR6 or its ligand CCL20 may therefore be a promising therapeutic strategy to alleviate atherosclerosis.