Lactadherin deficiency leads to apoptotic cell accumulation and accelerated atherosclerosis in mice
Lactadherin deficiency leads to apoptotic cell accumulation and accelerated atherosclerosis in mice
复制标题
DOI：
10.1161/circulationaha.106.662080
复制
发表时间：
2007-04-24
期刊：
影响因子：
37.8
通讯作者：
Mallat, Ziad
中科院分区：
文献类型：
--
作者：
Ait-Oufella, Hafid;Kinugawa, Kiyoka;Mallat, Ziad
背景-动脉粥样硬化是一种免疫炎症性疾病，然而，负责维持免疫调节的关键因素，在促炎环境知之甚少。方法和结果-在这里，我们表明，牛奶脂肪球-EGF因子8（Mfge 8，也被称为lactadherin）在正常和动脉粥样硬化的人动脉中表达，并参与吞噬清除凋亡细胞的腹腔巨噬细胞。在动脉粥样硬化的鼠模型中骨髓来源的Mfge 8的破坏导致凋亡碎片在全身和发展中的脂质病变内的大量积累。凋亡物质的积累与脾脏中白细胞介素-10的减少有关，但与脾脏和动脉粥样硬化动脉中干扰素-γ的产生有关。此外，我们报告了一个树突状细胞依赖性的改变自然调节T细胞功能的Mfge 8的情况下。这些事件与动脉粥样硬化的显着加速有关。结论-骨髓来源的细胞中缺乏Mfge 8会增强动脉粥样硬化中凋亡细胞尸体的积累，并改变保护性免疫反应，从而导致斑块加速发展。
Background - Atherosclerosis is an immunoinflammatory disease; however, the key factors responsible for the maintenance of immune regulation in a proinflammatory milieu are poorly understood.Methods and Results - Here, we show that milk fat globule-EGF factor 8 ( Mfge8, also known as lactadherin) is expressed in normal and atherosclerotic human arteries and is involved in phagocytic clearance of apoptotic cells by peritoneal macrophages. Disruption of bone marrow - derived Mfge8 in a murine model of atherosclerosis leads to substantial accumulation of apoptotic debris both systemically and within the developing lipid lesions. The accumulation of apoptotic material is associated with a reduction in interleukin-10 in the spleen but an increase in interferon-gamma production in both the spleen and the atherosclerotic arteries. In addition, we report a dendritic cell-dependent alteration of natural regulatory T-cell function in the absence of Mfge8. These events are associated with a marked acceleration of atherosclerosis.Conclusions - Lack of Mfge8 in bone marrow - derived cells enhances the accumulation of apoptotic cell corpses in atherosclerosis and alters the protective immune response, which leads to an acceleration of plaque development.