Department of Cardiology, Cardiovascular Key Laboratory of Zhejiang Province, Zhejiang University School of Medicine Second Affiliated Hospital, Hangzhou, China.
College of Information Science and Electronic Engineering, Zhejiang University, Hangzhou, China.
J Cell Mol Med. 2021 Aug;25(15):7280-7293. doi: 10.1111/jcmm.16757. Epub 2021 Jun 29.
Chemokine C-C motif ligand 7 (CCL7), a member of CC chemokine subfamily, plays pivotal roles in numerous inflammatory diseases. Hyper-activation of inflammation is an important characteristic of abdominal aortic aneurysm (AAA). Therefore, in the present study, we aimed to determine the effect of CCL7 on AAA formation. CCL7 abundance in aortic tissue and macrophage infiltration were both increased in angiotensin II (Ang II)-induced AAA mice. Ex vivo, CCL7 promoted macrophage polarization towards M1 phenotype. This effect was reversed by the blockage of CCR1, a receptor of CCL7. CCL7 up-regulated JAK2/STAT1 protein level in macrophage, and CCL7-induced M1 activation was suppressed by JAK2/STAT1 pathway inhibition. To verify the effect of CCL7 on AAA in vivo, either CCL7-neutralizing antibody (CCL7-nAb) or vehicles were intraperitoneally injected 24 hours prior to Ang II infusion and subsequently every three days for 4 weeks. CCL7-nAb administration significantly attenuated Ang II-induced luminal and external dilation as well as pathological remodelling. Immunostaining showed that CCL7-nAb administration significantly decreased aneurysmal macrophage infiltration. In conclusion, CCL7 contributed to Ang II-induced AAA by promoting M1 phenotype of macrophage through CCR1/JAK2/STAT1 signalling pathway.
趋化因子 C-C 基元配体 7（CCL7）是 CC 趋化因子亚家族的成员，在许多炎症性疾病中发挥关键作用。炎症的过度激活是腹主动脉瘤（AAA）的一个重要特征。因此，在本研究中，我们旨在确定 CCL7 对 AAA 形成的影响。在血管紧张素 II（Ang II）诱导的 AAA 小鼠中，主动脉组织中 CCL7 的丰度和巨噬细胞浸润均增加。在体外，CCL7 促进巨噬细胞向 M1 表型极化。这种作用被 CCL7 的受体 CCR1 阻断所逆转。CCL7 上调了巨噬细胞中的 JAK2/STAT1 蛋白水平，而 CCL7 诱导的 M1 激活被 JAK2/STAT1 通路抑制所抑制。为了验证 CCL7 在体内对 AAA 的影响，在 Ang II 输注前 24 小时和随后每 3 天腹腔内注射 CCL7 中和抗体（CCL7-nAb）或载体，共 4 周。CCL7-nAb 给药显著减轻了 Ang II 诱导的管腔和外膜扩张以及病理性重塑。免疫染色显示，CCL7-nAb 给药显著减少了动脉瘤性巨噬细胞浸润。总之，CCL7 通过 CCR1/JAK2/STAT1 信号通路促进巨噬细胞的 M1 表型，从而促进 Ang II 诱导的 AAA。
