AbstractImbalance of proinflammatory and anti-inflammatory responses plays a crucial role in the progression of abdominal aortic aneurysms. ILF3, a known modulator of the innate immune response, is involved in cardiovascular diseases. This study aims to investigate the role of ILF3 in abdominal aortic aneurysm formation.

摘要促炎和抗炎反应的不平衡在腹主动脉瘤的进展中起着至关重要的作用。ILF3是一种已知的先天免疫反应调节剂，与心血管疾病有关。本研究旨在探讨ILF3在腹主动脉瘤形成中的作用。

Here, we use multi-omics analyzes, transgenic male mice, and multiplex immunohistochemistry to unravel the underlying involvement of ILF3 in abdominal aortic aneurysms. The results show that macrophage ILF3 deficiency attenuates abdominal aortic aneurysm progression, while elevated macrophage ILF3 exacerbates abdominal aortic aneurysm lesions.

在这里，我们使用多组学分析，转基因雄性小鼠和多重免疫组织化学来揭示ILF3在腹主动脉瘤中的潜在参与。结果表明，巨噬细胞ILF3缺乏会减弱腹主动脉瘤的进展，而巨噬细胞ILF3升高会加剧腹主动脉瘤的病变。

Mechanistically, we reveal that macrophagic ILF3 increases NF-κB activity by hastening the decay of p105 mRNA, leading to amplified inflammation in macrophages. Meanwhile, ILF3 represses the anti-inflammatory action by inhibiting the Keap1-Nrf2 signaling pathway through facilitating the ILF3/eIF4A1 complex-mediated enhancement of Keap1 translational efficiency.

从机制上讲，我们发现巨噬细胞ILF3通过加速p105 mRNA的衰变来增加NF-κB活性，从而导致巨噬细胞炎症反应加剧。同时，ILF3通过促进ILF3/eIF4A1复合物介导的Keap1翻译效率的增强来抑制Keap1-Nrf2信号通路，从而抑制抗炎作用。

Moreover, Bardoxolone Methyl treatment alleviates the severity of abdominal aortic aneurysm lesions in the context of elevated ILF3 expression. Together, our findings underscore the significance of macrophage ILF3 in abdominal aortic aneurysm development and suggest its potential as a promising therapeutic target for abdominal aortic aneurysms..

此外，在ILF3表达升高的情况下，巴多索隆甲基治疗减轻了腹主动脉瘤病变的严重程度。总之，我们的研究结果强调了巨噬细胞ILF3在腹主动脉瘤发展中的重要性，并表明其作为腹主动脉瘤有希望的治疗靶点的潜力。。

IntroductionAbdominal aortic aneurysm (AAA) is a complex fatal vascular disease characterized by irreversible enlargement of the aortic diameter, accompanied by focal inflammation, turbulent proteolytic activities, and extracellular matrix (ECM) degradation1,2,3. Inflammatory cell infiltration and intense inflammatory response play crucial roles in AAA initiation and progression1,4.

引言腹主动脉瘤（AAA）是一种复杂的致命性血管疾病，其特征是主动脉直径不可逆地增大，伴有局灶性炎症，湍流蛋白水解活性和细胞外基质（ECM）降解1,2,3。炎性细胞浸润和强烈的炎症反应在AAA的发生和发展中起着至关重要的作用1,4。

Recently, there has been an emphasis on the role of immune regulation in maintaining the inflammatory balance during AAA progression5. Clinical investigations have found that aneurysm size in patients with AAA is dependent on the imbalance of pro-inflammatory and anti-inflammatory responses6. Moreover, serum levels of the pro-inflammatory cytokine interleukin 6 (IL-6) were significantly increased in AAA patients, in contrast to a notable reduction in the anti-inflammatory cytokine Interleukin-10 (IL-10)2.

最近，人们强调了免疫调节在AAA进展期间维持炎症平衡的作用5。临床研究发现，AAA患者的动脉瘤大小取决于促炎和抗炎反应的不平衡6。此外，AAA患者血清促炎细胞因子白细胞介素6（IL-6）水平显着升高，而抗炎细胞因子白细胞介素10（IL-10）2显着降低。

Similar findings have been observed in human AAA explant cultures and murine models5,7. Recent microarray-based gene expression studies have confirmed that AAA is a chronic inflammatory disease, with the actions of activated macrophage subsets playing a significant role7. Macrophage infiltration into the adventitia serves as a seminal event in the onset of AAA pathogenesis, which mediates inflammatory homeostasis by producing chemokines and cytokines that is critical to aneurysmal progression8,9.

在人类AAA外植体培养物和小鼠模型中也观察到类似的发现5,7。最近基于微阵列的基因表达研究证实，AAA是一种慢性炎症性疾病，活化的巨噬细胞亚群的作用起着重要作用7。巨噬细胞浸润到外膜中是AAA发病机制发生的重要事件，它通过产生对动脉瘤进展至关重要的趋化因子和细胞因子来介导炎症稳态8,9。

However, the specific molecular mechanism of macrophage infiltration and inflammation in aneurysm dilatation are not yet fully delineated. Besides, no explicit therapy targeting the immunoinflammatory response is currently available to impede excessive inflammatory response and remodeling of the abdominal aortic wall.Interleukin enhancer-binding factor 3 (ILF3) is an RNA-binding protein initially i.

然而，动脉瘤扩张中巨噬细胞浸润和炎症的具体分子机制尚未完全阐明。此外，目前还没有针对免疫炎症反应的明确疗法来阻止过度的炎症反应和腹主动脉壁的重塑。白细胞介素增强子结合因子3（ILF3）最初是一种RNA结合蛋白。

Data availability

数据可用性

The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the iProX partner repository with the dataset identifier PXD047695. IP-MS datasets are available via ProteomeXchange with identifiers PXD047694. All sequencing data generated in this study have been deposited in the NCBI Sequence Read Archive under the BioProject ID PRJNA1050581 for Ribo-seq, PRJNA1050631 for RIP-seq.

质谱蛋白质组学数据已通过iProX合作伙伴存储库保存到ProteomeXchange Consortium，数据集标识符为PXD047695。IP-MS数据集可通过ProteomeXchange获得，标识符为PXD047694。本研究中产生的所有测序数据均已保存在NCBI序列读取档案中，生物项目ID PRJNA1050581用于Ribo-seq，PRJNA1050631用于RIP-seq。

All other data are available in the article and its Supplementary files or from the corresponding author upon request. Source data are provided with this paper..

所有其他数据均可在文章及其补充文件中获得，或应要求从通讯作者处获得。本文提供了源数据。。

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Download referencesAcknowledgementsThis work was supported by the National Natural Science Foundation of China (No. 82370455 and 82200466), the National Key R & D Program of China (No.2017YFC0908700, 2017YFC0908703 and 2017YFC1308000), the Taishan Scholar Project of Shandong Province of China (No.ts20190972, No.tsqn202306377), Natural Science Foundation of Shandong Province (No.ZR2022QH296), Key Clinical Research project of Clinical Research Center of Shandong University (No.2020SDUCRCA016), and Academic promotion program of Shandong First Medical University (No.2021QL021).Author informationAuthor notesThese authors contributed equally: Zhao-yang Wang, Jie Cheng, Ying Wang, Hai-tao Yuan, Shao-jie Bi.Authors and AffiliationsThe Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, ChinaZhao-yang Wang, Jie Cheng, Ying Wang, Shuang-xi Wang, Ya-min Hou, Xu Zhang, Bo-han Xu, Ze-ying Wang, Yun Zhang & Ming-xiang ZhangDepartment of Cardiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, ChinaZhao-yang Wang & Hai-tao YuanDepartment of Cardiology, the Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, ChinaShao-jie BiDepartment of Cardiovascular Surgery, Beijing Anzhen Hospital, Capital Medical University, Beijing, ChinaWen-jian JiangDepartment of Emergency and Chest Pain Center, Qilu Hospital, Shandong University, Jinan, ChinaYu-guo ChenAuthorsZhao-yang WangView author publicationsYou can also search for this author in.

下载参考文献致谢这项工作得到了国家自然科学基金（编号82370455和82200466），国家重点研发计划（编号2017YFC090870017YFC0908703和2017YFC1308000），山东省泰山学者项目（编号ts20190972，编号tsqn202306377），山东省自然科学基金（编号ZR202QH296），山东大学临床研究中心重点临床研究项目（编号2020SDUCRCA016）和山东第一医科大学学术推广计划（编号2021QL021）。作者信息作者注：这些作者做出了同样的贡献：王昭阳，程杰，王英，袁海涛，毕绍杰。作者和附属机构中国教育部，中国国家卫生委员会和中国医学科学院心血管重塑与功能研究重点实验室，山东大学齐鲁医院心内科，济南，中国赵阳，王杰，王英，王双喜，侯亚敏，张旭，徐伯翰，王泽英，张云章和张明祥山东省第一医科大学附属医院心内科，山东济南，中国赵阳王和袁海涛齐鲁第二医院心内科山东大学医学院，济南，山东邵杰首都医科大学北京安贞医院心血管外科，北京，齐鲁医院急诊与胸痛中心，山东大学，济南，中国，陈玉国，作者赵阳，王维，作者出版物你也可以在中搜索这位作者。

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PubMed Google ScholarContributionsZ.W., J.C., Y.W., H.Y., and S.B. contributed equally to this work. Z.W., M.Z., and Y.C. conceived the project. Z.W. and M.Z. wrote the manuscript. Y.Z., W.J., and M.Z. supervised the study. Z.W., J.C., H.Y., S.B., S.W., and Ze.W. performed human studies and carried out analyses.

。W、 ，J.C.，Y.W.，H.Y。和S.B.对这项工作做出了同样的贡献。Z.W.，M.Z。和Y.C.构思了这个项目。Z、 W.和M.Z.写了手稿。Y、 Z.，W.J。和M.Z.监督了这项研究。Z、 W.，J.C.，H.Y.，S.B.，S.W。和Ze。W、 进行了人体研究并进行了分析。

Z.W., J.C., Y.W., B.X., X.Z., and Y.H. performed animal experiments and prepared figures. Z.W., J.C., and M.Z. interpreted the results. All authors reviewed the results and approved the final version of the manuscript.Corresponding authorsCorrespondence to.

Z、 W.，J.C.，Y.W.，B.X.，X.Z。和Y.H.进行了动物实验并准备了数字。Z、 W.，J.C。和M.Z.解释了结果。所有作者都审查了结果并批准了稿件的最终版本。通讯作者通讯。

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Reprints and permissionsAbout this articleCite this articleWang, Zy., Cheng, J., Wang, Y. et al. Macrophage ILF3 promotes abdominal aortic aneurysm by inducing inflammatory imbalance in male mice.

。，Cheng，J.，Wang，Y.等人。巨噬细胞ILF3通过诱导雄性小鼠的炎症失衡来促进腹主动脉瘤。

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