Targeted disruption of the scavenger receptor and chemokine CXCL16 accelerates atherosclerosis
Targeted disruption of the scavenger receptor and chemokine CXCL16 accelerates atherosclerosis
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DOI：
10.1161/circulationaha.105.540583
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发表时间：
2006-08-08
期刊：
影响因子：
37.8
通讯作者：
Charo, Israel F.
中科院分区：
文献类型：
--
作者：
Aslanian, Ara M.;Charo, Israel F.
巨噬细胞清道夫受体对氧化低密度脂蛋白（OxLDL）的摄取被认为是泡沫细胞形成的关键过程，泡沫细胞是早期动脉粥样硬化病变的标志。CXCL 16/磷脂酰丝氨酸和OxLDL的清道夫受体是一种多功能趋化因子，其对膜结合构型中的氧化脂质表现出清道夫受体活性，并且可以脱落以充当辅助性T细胞1极化T淋巴细胞的化学引诱物。这些特性以及CXCL 16在人类和小鼠动脉粥样硬化中的表达表明CXCL 16在动脉粥样硬化中发挥作用。方法和结果-为了检查CXCL 16在斑块形成中的作用，我们创建了CXCL 16缺陷小鼠（CXCL 16（-/-）），并将它们与低密度脂蛋白受体（LDLR-/-）缺陷的小鼠交配。在体外，来自CXCL 16（-/-）小鼠的巨噬细胞结合和内化OxLDL的能力显著降低。我们发现CXCL 16（-/-）/LDLR-/-小鼠加速了动脉粥样硬化，增强了巨噬细胞向主动脉弓的募集，单核细胞趋化蛋白-1和肿瘤坏死因子-α的mRNA更丰富。结论-这些数据表明，体内CXCL 16介导的清道夫受体活性具有抗动脉粥样硬化作用，并且他们与记录A类清道夫受体和CD 36缺陷小鼠预防动脉粥样硬化的研究形成对比。
Background - The uptake of oxidized low-density lipoprotein ( OxLDL) by macrophage scavenger receptors is thought to be a key process in the formation of foam cells, the hallmark of early atherosclerotic lesions. CXCL16/scavenger receptor for phosphatidylserine and OxLDL is a multifunctional chemokine that exhibits scavenger receptor activity toward oxidized lipids in a membrane-bound configuration and may be shed to serve as a chemoattractant for T helper 1 - polarized T lymphocytes. These properties, as well as the expression of CXCL16 in human and mouse atheroma, suggest that CXCL16 plays a role in atherosclerosis.Methods and Results - To examine the role of CXCL16 in plaque formation, we created CXCL16-deficient mice ( CXCL16(-/-)) and bred them with mice deficient in the LDL receptor ( LDLR-/-). In vitro, macrophages from CXCL16(-/-) mice have a significant reduction in the capacity to bind and internalize OxLDL. We found that CXCL16(-/-)/LDLR-/- mice have accelerated atherosclerosis, enhanced macrophage recruitment to the aortic arch, and more abundant mRNA for monocyte chemotactic protein-1 and tumor necrosis factor-alpha.Conclusions - These data suggest that scavenger receptor activity mediated by CXCL16 in vivo is atheroprotective, and they contrast with studies that document protection from atherosclerosis in scavenger receptor class A - and CD36-deficient mice.