Requirement for CD154 in the progression of atherosclerosis
Requirement for CD154 in the progression of atherosclerosis
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DOI：
10.1038/15271
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发表时间：
1999-11-01
期刊：
影响因子：
82.9
通讯作者：
Flavell, RA
中科院分区：
文献类型：
--
作者：
Lutgens, E;Gorelik, L;Flavell, RA
动脉粥样硬化是一种大动脉的全身性疾病，炎症通路的激活在其发病机制中很重要（1）。越来越多的证据支持CD 40-CD 154相互作用在动脉粥样硬化中的重要性（2，3），最初已知的相互作用在主要免疫反应（4）和自身免疫性疾病（5）中是必不可少的。CD 40存在于体外动脉粥样硬化衍生细胞和原位人动脉粥样硬化中（6）。在体外，动脉粥样硬化相关细胞上的CD 40的连接激活了趋化因子（6）、细胞因子（6）、基质金属蛋白酶（7，8）、粘附分子（9，10）和组织因子的产生：这些物质负责病变进展和斑块不稳定（1）。向低密度脂蛋白受体缺陷小鼠给予抗CD 154抗体已显示可减少动脉粥样硬化并降低T淋巴细胞和巨噬细胞含量;然而，仅研究了初始病变（3）。在这里，我们确定了在初始和晚期动脉粥样硬化病变中ApoE（-/-）小鼠中CD 154基因破坏的影响。斑块面积减少550%。与以前的报告相反，最初的病变发展没有受到影响。CD 154（-/-）ApoE（-/-）小鼠中的晚期斑块具有含脂较少、富含胶原蛋白、稳定的斑块表型，T淋巴细胞/巨噬细胞含量降低。这些数据表明，CD 40-CD 154信号传导在晚期动脉粥样硬化变化中是重要的，如脂质核心形成和斑块不稳定。
Atherosclerosis is a systemic disease of the large arteries, and activation of inflammatory pathways is important in its pathogenesis(1). Increasing evidence supports the importance of CD40-CD154 interactions in atherosclerosis(2,3), interactions originally known to be essential in major immune reactions(4) and autoimmune diseases(5). CD40 is present on atheroma-derived cells in vitro and in human atheromata in situ(6). Ligation of CD40 on atheroma-associated cells in vitro activates the production of chemokines(6), cytokines(6), matrix metalloproteinases(7,8), adhesion molecules(9,10) and tissue factor: substances responsible for lesion progression and plaque destabilization(1). Administration of antibody against CD154 to low-density lipoprotein receptor-deficient mice has been shown to reduce atherosclerosis and decrease T-lymphocyte and macrophage content; however, only initial lesions were studied(3). Here, we determined the effect of genetic disruption of CD154 in ApoE(-/-) mice in both initial and advanced atherosclerotic lesions. Plaque area was reduced 550%. In contrast to previous reports, initial lesion development was not affected. Advanced plaques in CD154(-/-)ApoE(-/-) mice had a less-lipid-containing, collagen-rich, stable plaque phenotype, with a reduced T-lymphocyte/macrophage content. These data indicate that CD40-CD154 signaling is important in late atherosclerotic changes, such as lipid core formation and plaque destabilization.