Wan Wuzhou, Liu Qian, Lionakis Michail S, Marino Ana Paula M P, Anderson Stasia A, Swamydas Muthulekha, Murphy Philip M
Molecular Signaling Section, Laboratory of Molecular Immunology (LMI), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, USA.
Fungal Pathogenesis Unit, Laboratory of Clinical Infectious Diseases, NIAID, NIH, Bethesda, MD, USA.
Cardiovasc Res. 2015 Jun 1;106(3):478-87. doi: 10.1093/cvr/cvv124. Epub 2015 Apr 8.
Atypical chemokine receptor 1 (Ackr1; previously known as the Duffy antigen receptor for chemokines or Darc) is thought to regulate acute inflammatory responses in part by scavenging inflammatory CC and CXC chemokines; however, evidence for a role in chronic inflammation has been lacking. Here we investigated the role of Ackr1 in chronic inflammation, in particular in the setting of atherogenesis, using the apolipoprotein E-deficient (ApoE(-/-)) mouse model.
Ackr1(-/-)ApoE(-/-) and Ackr1(+/+)ApoE(-/-) littermates were obtained by crossing ApoE(-/-) mice and Ackr1(-/-) mice on a C57BL/6J background. Ackr1 (+/+)ApoE(-/-)mice fed a Western diet up-regulated Ackr1 expression in the aorta and had markedly increased atherosclerotic lesion size compared with Ackr1(-/-)ApoE(-/-) mice. This difference was observed in both the whole aorta and the aortic root in both early and late stages of the model. Ackr1 deficiency did not affect serum cholesterol levels or macrophage, collagen or smooth muscle cell content in atherosclerotic plaques, but significantly reduced the expression of Ccl2 and Cxcl1 in the whole aorta of ApoE(-/-) mice. In addition, Ackr1 deficiency resulted in a modest decrease in T cell subset frequency and inflammatory mononuclear phagocyte content in aorta and blood in the model.
Ackr1 deficiency appears to be protective in the ApoE knockout model of atherogenesis, but it is associated with only modest changes in cytokine and chemokine expression as well as T-cell subset frequency and inflammatory macrophage content.
非典型趋化因子受体1（Ackr1；以前称为趋化因子达菲抗原受体或Darc）被认为部分通过清除炎症性CC和CXC趋化因子来调节急性炎症反应；然而，其在慢性炎症中的作用证据一直不足。在此，我们使用载脂蛋白E缺陷（ApoE(-/-)）小鼠模型研究了Ackr1在慢性炎症中的作用，特别是在动脉粥样硬化形成过程中的作用。
通过将C57BL/6J背景的ApoE(-/-)小鼠与Ackr1(-/-)小鼠杂交，获得了Ackr1(-/-)ApoE(-/-)和Ackr1(+/+)ApoE(-/-)同窝小鼠。与Ackr1(-/-)ApoE(-/-)小鼠相比，喂食西式饮食的Ackr1(+/+)ApoE(-/-)小鼠主动脉中Ackr1表达上调，动脉粥样硬化病变大小显著增加。在模型的早期和晚期，在整个主动脉和主动脉根部均观察到这种差异。Ackr1缺陷不影响血清胆固醇水平或动脉粥样硬化斑块中的巨噬细胞、胶原蛋白或平滑肌细胞含量，但显著降低了ApoE(-/-)小鼠整个主动脉中Ccl2和Cxcl1的表达。此外，Ackr1缺陷导致模型中主动脉和血液中T细胞亚群频率以及炎性单核吞噬细胞含量适度降低。
在ApoE基因敲除的动脉粥样硬化模型中，Ackr1缺陷似乎具有保护作用，但它仅与细胞因子和趋化因子表达以及T细胞亚群频率和炎性巨噬细胞含量的适度变化有关。
