Deficiency of ITGAM Attenuates Experimental Abdominal Aortic Aneurysm in Mice.
Deficiency of ITGAM Attenuates Experimental Abdominal Aortic Aneurysm in Mice.
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ITGAM 缺乏可减轻小鼠实验性腹主动脉瘤
DOI：
10.1161/jaha.120.019900
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发表时间：
2021-04-06
影响因子：
5.4
通讯作者：
Fu W
中科院分区：
文献类型：
--
作者：
Zhou M;Wang X;Shi Y;Ding Y;Li X;Xie T;Shi Z;Fu W
整合素αM （CD11b）是由整合素亚单位αM （Integrin Subunit Alpha M， ITGAM）基因编码的，它不仅是单核细胞的表面标记物，也是必不可少的粘附分子。在这项研究中，我们研究了CD11b对实验性腹主动脉瘤的影响及其潜在的机制。方法与结果ITGAM（‐/‐）小鼠的腹主动脉瘤发生率未显著低于对照组小鼠。然而，敲除CD11b降低了腹主动脉最大直径、巨噬细胞浸润、基质金属蛋白酶- 9表达以及弹性蛋白和胶原蛋白降解。此外，在ITGAM（‐/‐）小鼠的外周血和腹主动脉中均发现IL - 6的低表达，表明CD11b与腹主动脉瘤炎症反应之间存在生物学相关性。在体外，粘附内皮细胞的ITGAM（‐/‐）骨髓源性巨噬细胞（BMDMs）的数量明显低于野生型BMDMs的数量。此外，CD11b单克隆抗体和CD11b激动剂白细胞粘附素- 1分别减少和增加了粘附的野生型BMDMs的数量。通过RNA测序，发现与白细胞跨内皮迁移相关的基因在ITGAM（‐/‐）bmdm中下调。此外，免疫沉淀-质谱分析预测Akt通路可能是ITGAM（‐/‐）BMDMs迁移能力受损的原因。Akt激活降低，Akt激动剂SC79部分恢复了ITGAM（‐/‐）BMDMs的跨内皮迁移功能。结论scd11b可能通过介导循环单核/巨噬细胞的内皮细胞粘附和跨内皮迁移促进腹主动脉瘤的发生发展。
BackgroundIntegrin αM (CD11b), which is encoded by the Integrin Subunit Alpha M (ITGAM) gene, is not only a surface marker of monocytes but also an essential adhesion molecule. In this study, we investigated the effect of CD11b on experimental abdominal aortic aneurysm and the potential underlying mechanisms.Methods and ResultsThe incidence of abdominal aortic aneurysm was not significantly lower in ITGAM(‐/‐) mice than in control mice. Nevertheless, knockout of CD11b reduced the maximum abdominal aortic diameter, macrophage infiltration, matrix metalloproteinase‐9 expression, and elastin and collagen degradation. Additionally, lower expression of IL‐6 was found in both the peripheral blood and abdominal aortas of ITGAM(‐/‐) mice, indicating a biological correlation between CD11b and the inflammatory response in abdominal aortic aneurysm. In vitro, the number of ITGAM(‐/‐) bone marrow–derived macrophages (BMDMs) that adhered to endothelial cells was significantly lower than the number of wild‐type BMDMs. Moreover, the CD11b monoclonal antibody and CD11b agonist leukadherin‐1 decreased and increased the number of adherent wild‐type BMDMs, respectively. Through RNA sequencing, genes associated with leukocyte transendothelial migration were found to be downregulated in ITGAM(‐/‐) BMDMs. Furthermore, immunoprecipitation–mass spectrometry analysis predicted that the Akt pathway might be responsible for the impaired transmigratory ability of ITGAM(‐/‐) BMDMs. The reduced activation of Akt was then confirmed, and the Akt agonist SC79 partially rescued the transendothelial migratory function of ITGAM(‐/‐) BMDMs.ConclusionsCD11b might promote the development and progression of abdominal aortic aneurysm by mediating the endothelial cells adhesion and transendothelial migration of circulating monocytes/macrophages.