Up-regulated expression of the CXCR2 ligand KC/GRO-α in atherosclerotic lesions plays a central role in macrophage accumulation and lesion progression
Up-regulated expression of the CXCR2 ligand KC/GRO-α in atherosclerotic lesions plays a central role in macrophage accumulation and lesion progression
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DOI：
10.2353/ajpath.2006.040748
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发表时间：
2006-04-01
影响因子：
6
通讯作者：
Terkeltaub, RA
中科院分区：
文献类型：
--
作者：
Boisvert, WA;Rose, DM;Terkeltaub, RA
巨噬细胞介导的炎症是动脉粥样硬化的核心。我们之前已经确定CXC趋化因子受体CXCR2参与晚期动脉粥样硬化。我们试图确定CXCR2的配体之一KC/GRO-alpha是否也可以调节动脉粥样硬化。生成KC/ gro - α(-/-)小鼠，并与易发生动脉粥样硬化的LDLR-/-小鼠交配。缺乏KC/GRO-a的小鼠动脉粥样硬化显著减少；然而，这种减少仅是先前在白细胞中缺乏CXCR2的小鼠中所见的大约一半。为了确定CXCR2是否参与动脉粥样硬化的早期形成，我们在LDLR-/-背景下生成白细胞特异性CXCR2（-/-）嵌合小鼠。这些小鼠的早期脂肪条纹病变形成不受白细胞CXCR2缺乏的影响，而当动脉粥样硬化进展到中间阶段时，缺乏白细胞CXCR2的小鼠的病变发展较少。巨噬细胞;在白细胞CXCR2-/-小鼠的病变中相对稀少，尽管MCP-1表达强劲。这些研究表明，KC/ gro - α /CXCR2在巨噬细胞募集到早期动脉粥样硬化病变中并不起关键作用，但动脉中KC/ gro - α和白细胞特异性CXCR2的表达对巨噬细胞积累至关重要。在已确定的脂肪条纹病变中。
Macrophage-mediated inflammation is central to atherogenesis. We have determined previously that the CXC chemokine receptor CXCR2 is involved in advanced atherosclerosis. We sought to determine whether one of the ligands of CXCR2, KC/GRO-alpha, can also modulate atherogenesis. KC/GRO-alpha(-/-) mice were generated and mated with the atherosclerosis-prone LDLR-/- mice. There was a significant reduction in atherosclerosis in mice lacking KC/GRO-a; however, this reduction was only approximately half that seen previously in mice lacking CXCR2 in the leukocyte. To determine whether CXCR2 is involved in the early formation of atherosclerosis, leukocyte-specific CXCR2(-/-) chimeric mice on LDLR-/- background were generated. Early fatty streak lesion formation in these mice was not affected by leukocyte CXCR2 deficiency whereas lesions were less developed in mice lacking leukocyte CXCR2 when atherosclerosis was allowed to progress to the intermediate stage. Macrophages; were relatively sparse in the lesions of leukocyte CXCR2-/- mice despite robust MCP-1 expression. These studies indicate that KC/ GRO-alpha/CXCR2 does not play a critical role in recruitment of macrophages into early atherosclerotic lesions but both arterial KC/GRO-a and leukocyte-specific CXCR2 expression are central to macrophage accumulation. in established fatty streak lesions.