TRAF5 Deficiency Accelerates Atherogenesis in Mice by Increasing Inflammatory Cell Recruitment and Foam Cell Formation
TRAF5 Deficiency Accelerates Atherogenesis in Mice by Increasing Inflammatory Cell Recruitment and Foam Cell Formation
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DOI：
10.1161/circresaha.110.219295
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发表时间：
2010-09-17
影响因子：
20.1
通讯作者：
Zirlik, Andreas
中科院分区：
文献类型：
--
作者：
Missiou, Anna;Rudolf, Philipp;Zirlik, Andreas
理论基础：肿瘤坏死因子受体相关因子（TRAFs）是肿瘤坏死因子/白细胞介素-1/ toll样受体超家族的细胞质衔接蛋白。该家族的配体包括多种重要的细胞因子，如TNFα、CD40L和白细胞介素-1β，可促进慢性炎症性疾病，如动脉粥样硬化。我们最近报道了TRAF5在小鼠和人类动脉粥样硬化中的过表达，并且TRAF5促进培养的内皮细胞和巨噬细胞的炎症功能。目的：验证体内TRAF5调控动脉粥样硬化的假说。方法和结果：令人惊讶的是，食用高胆固醇饮食18周的TRAF5 - / - /LDLR - / -小鼠的动脉粥样硬化病变明显大于TRAF5+/+/LDLR - / -对照组。traf5缺陷动物的斑块含有更多的脂质和巨噬细胞，而平滑肌细胞和胶原蛋白保持不变。内皮细胞或白细胞中TRAF5的缺乏增强了炎症细胞对内皮的粘附，在体外和体内活体显微镜成像的小鼠血管中进行动态粘附试验。TRAF5缺乏也增加了粘附分子和趋化因子的表达，增强了巨噬细胞脂质摄取和泡沫细胞的形成。这些发现与JNK激活的增加相吻合，并且似乎与TRAF2无关。最后，与健康对照组相比，稳定型或急性冠心病患者血液中TRAF5 mRNA的含量显著降低。结论：出乎意料的是，TRAF5缺乏加速了小鼠动脉粥样硬化的发生，这可能是由炎症细胞向血管壁募集增加和泡沫细胞形成增强介导的。
Rationale:Tumor necrosis factor receptor–associated factors (TRAFs) are cytoplasmic adaptor proteins for the TNF/interleukin-1/Toll-like receptor superfamily. Ligands of this family comprise multiple important cytokines such as TNFα, CD40L, and interleukin-1β that promote chronic inflammatory diseases such as atherosclerosis. We recently reported overexpression of TRAF5 in murine and human atheromata and that TRAF5 promotes inflammatory functions of cultured endothelial cells and macrophages.Objective:This study tested the hypothesis that TRAF5 modulates atherogenesis in vivo.Methods and Results:Surprisingly, TRAF5−/−/LDLR−/−mice consuming a high-cholesterol diet for 18 weeks developed significantly larger atherosclerotic lesions than did TRAF5+/+/LDLR−/−controls. Plaques of TRAF5-deficient animals contained more lipids and macrophages, whereas smooth muscle cells and collagen remained unchanged. Deficiency of TRAF5 in endothelial cells or in leukocytes enhanced adhesion of inflammatory cells to the endothelium in dynamic adhesion assays in vitro and in murine vessels imaged by intravital microscopy in vivo. TRAF5 deficiency also increased expression of adhesion molecules and chemokines and potentiated macrophage lipid uptake and foam cell formation. These findings coincided with increased activation of JNK and appeared to be independent of TRAF2. Finally, patients with stable or acute coronary heart disease had significantly lower amounts of TRAF5 mRNA in blood compared with healthy controls.Conclusions:Unexpectedly, TRAF5 deficiency accelerates atherogenesis in mice, an effect likely mediated by increased inflammatory cell recruitment to the vessel wall and enhanced foam cell formation.