Activation of an Innate Immune Receptor, Nod1, Accelerates Atherogenesis in Apoe-/- Mice
Activation of an Innate Immune Receptor, Nod1, Accelerates Atherogenesis in Apoe-/- Mice
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DOI：
10.4049/jimmunol.1302841
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发表时间：
2015-01-15
影响因子：
4.4
通讯作者：
Hara, Toshiro
中科院分区：
文献类型：
--
作者：
Kanno, Shunsuke;Nishio, Hisanori;Hara, Toshiro
动脉粥样硬化本质上是在过量脂质存在的情况下的血管炎症过程。我们最近报道，口服核苷酸结合的寡聚化结构域(NOD)-1配体FK565在体内诱导血管炎症。然而，还没有研究证明Nod1与体内动脉粥样硬化之间的联系。为了研究NOD1在动脉粥样硬化形成中的潜在作用，我们间歇给载脂蛋白E基因敲除(APOE(-/-))小鼠口服FK565 4wk，并进行了主动脉根部和主动脉的动脉粥样硬化病变的量化、免疫组织化学分析和基于基因芯片的主动脉根部基因表达谱分析。FK565给药可加速APOE(-/-)小鼠动脉粥样硬化的形成，其作用依赖于骨髓移植实验中非骨髓源细胞中的Nod1。免疫组织化学研究显示，巨噬细胞和CD3T细胞在主动脉根部斑块内积聚增加。主动脉根部基因表达分析显示，在动脉粥样硬化形成的早期，CCL5基因显著上调，CCL5拮抗剂治疗显著抑制了FK565注射APOE(-/-)小鼠动脉粥样硬化的加速。此外，与APOE(-/-)小鼠相比，APOE和Nod1双基因敲除小鼠在9wk时动脉粥样硬化病变的发展从早期就减少了，进展缓慢，CCL5mRNA水平显著降低。本研究的数据表明，非骨髓源性细胞中的Nod1信号通路参与了动脉粥样硬化的发展。
Atherosclerosis is essentially a vascular inflammatory process in the presence of an excess amount of lipid. We have recently reported that oral administration of a nucleotide-binding oligomerization domain (Nod)-1 ligand, FK565, induced vascular inflammation in vivo. No studies, however, have proven the association between Nod1 and atherosclerosis in vivo. To investigate a potential role of NOD1 in atherogenesis, we orally administered FK565 to apolipoprotein E knockout (Apoe(-/-)) mice for 4 wk intermittently and performed quantification of atherosclerotic lesions in aortic roots and aortas, immunohistochemical analyses, and microarray-based gene expression profiling of aortic roots. FK565 administration accelerated the development of atherosclerosis in Apoe(-/-) mice, and the effect was dependent on Nod1 in non-bone marrow origin cells by bone marrow transplantation experiments. Immunohistochemical studies revealed the increases in the accumulation of macrophages and CD3 T cells within the plaques in aortic roots. Gene expression analyses of aortic roots demonstrated a marked upregulation of the Ccl5 gene during early stage of atherogenesis, and the treatment with Ccl5 antagonist significantly inhibited the acceleration of atherosclerosis in FK565-administered Apoe(-/-) mice. Additionally, as compared with Apoe(-/-) mice, Apoe and Nod1 double-knockout mice showed reduced development of atherosclerotic lesions from the early stage as well as their delayed progression and a significant reduction in Ccl5 mRNA levels at 9 wk of age. Data in the present study show that the Nod1 signaling pathway in non-bone marrow-derived cells contributes to the development of atherosclerosis.