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Macrophage ILF3 promotes abdominal aortic aneurysm by inducing inflammatory imbalance in male mice.

ABSTRACT: Imbalance 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. 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. 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. 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.

SUBMITTER: Wang ZY

PROVIDER: S-EPMC11344041 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature

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Macrophage ILF3 promotes abdominal aortic aneurysm by inducing inflammatory imbalance in male mice.

Wang Zhao-Yang ZY Cheng Jie J Wang Ying Y Yuan Hai-Tao HT Bi Shao-Jie SJ Wang Shuang-Xi SX Hou Ya-Min YM Zhang Xu X Xu Bo-Han BH Wang Ze-Ying ZY Zhang Yun Y Jiang Wen-Jian WJ Chen Yu-Guo YG Zhang Ming-Xiang MX

Nature communications 20240823 1

Imbalance 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. 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 ...[more]

PMID: 39179537

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Project description:The long noncoding RNA (lncRNA) CARMN (cardiac mesoderm enhancer associated noncoding RNA) is a highly conserved lncRNA that expresses primarily by smooth muscle cells (SMCs). Recent literature demonstrates that CARMN plays a critical role in the differentiation and maintaining of the contractile state of vascular SMCs. Because aortic SMCs show diminished contractile proteins in abdominal aortic aneurysms (AAAs), we hypothesize that the expression of CARMN is downregulated in the aortic wall affected by aneurysm. In this study, we analyzed publicly available single-cell or bulk RNA sequencing data comparing healthy and aneurysmal mouse aortic tissues. In both healthy and diseased aortas, Carmn expression was enriched in SMCs characterized by the high expression of SMC-specific contractile proteins including Myh11 and Acta2. Carmn expression levels varied among the sub-clusters of SMCs and consequently along the aortic tree. Comparing to the corresponding sham aorta, aortas from 3 distinct AAA models contained less Carmn. To validate the Carmn downregulation, we induced AAA using the Angiotensin II and CaCl2 models. In situ hybridization showed that Carmn mRNA located in the nuclei of SMCs and became downregulated within a few days following the aneurysm induction. Mechanistically, we tested whether Carmn expression is regulated by infiltrating macrophages --- the predominant inflammatory cells found in aneurysmal tissues --- by treating healthy mouse aortic SMCs with media conditioned by macrophages primed with pro-inflammatory or anti-inflammatory cytokines. PCR analysis showed that inflammatory macrophages reduced the expression of Carmn and contractile genes including Myh11 and Acta2. Taken together, our results from bioinformatic and experimental analyses demonstrate that Carmn is downregulated in different AAA models, likely by inflammatory macrophages. The negative regulation of Carmn in AAA tissues may explain at least in part the loss of SMC contractile state during the pathogenesis of this progressive degenerative disease.

Project description:Inflammation plays a major role in the pathogenesis of several vascular pathologies, including abdominal aortic aneurysm (AAA). Evaluating the role of inflammation in AAA pathobiology and potentially outcome in vivo requires non-invasive tools for high-resolution imaging. We investigated the feasibility of X-ray computed tomography (CT) imaging of phagocytic activity using nanoparticle contrast agents to predict AAA outcome. Methods: Uptake of several nanoparticle CT contrast agents was evaluated in a macrophage cell line. The most promising agent, Exitron nano 12000, was further characterized in vitro and used for subsequent in vivo testing. AAA was induced in Apoe-/- mice through angiotensin II (Ang II) infusion for up to 4 weeks. Nanoparticle biodistribution and uptake in AAA were evaluated by CT imaging in Ang II-infused Apoe-/- mice. After imaging, the aortic tissue was harvested and used from morphometry, transmission electron microscopy and gene expression analysis. A group of Ang II-infused Apoe-/- mice underwent nanoparticle-enhanced CT imaging within the first week of Ang II infusion, and their survival and aortic external diameter were evaluated at 4 weeks to address the value of vessel wall CT enhancement in predicting AAA outcome. Results: Exitron nano 12000 showed specific uptake in macrophages in vitro. Nanoparticle accumulation was observed by CT imaging in tissues rich in mononuclear phagocytes. Aortic wall enhancement was detectable on delayed CT images following nanoparticle administration and correlated with vessel wall CD68 expression. Transmission electron microscopy ascertained the presence of nanoparticles in AAA adventitial macrophages. Nanoparticle-induced CT enhancement on images obtained within one week of AAA induction was predictive of AAA outcome at 4 weeks. Conclusions: By establishing the feasibility of CT-based molecular imaging of phagocytic activity in AAA, this study links the inflammatory signal on early time point images to AAA evolution. This readily available technology overcomes an important barrier to cross-sectional, longitudinal and outcome studies, not only in AAA, but also in other cardiovascular pathologies and facilitates the evaluation of modulatory interventions, and ultimately upon clinical translation, patient management.

Project description:BackgroundMacrophage activation plays a critical role in abdominal aortic aneurysm (AAA) development. However, molecular mechanisms controlling macrophage activation and vascular inflammation in AAA remain largely unknown. The objective of the study was to identify novel mechanisms underlying adenosine deaminase acting on RNA (ADAR1) function in macrophage activation and AAA formation.MethodsAortic transplantation was conducted to determine the importance of nonvascular ADAR1 in AAA development/dissection. Ang II (Angiotensin II) infusion of ApoE-/- mouse model combined with macrophage-specific knockout of ADAR1 was used to study ADAR1 macrophage-specific role in AAA formation/dissection. The relevance of macrophage ADAR1 to human AAA was examined using human aneurysm specimens. Moreover, a novel humanized AAA model was established to test the role of human macrophages in aneurysm formation in human arteries.ResultsAllograft transplantation of wild-type abdominal aortas to ADAR1+/- recipient mice significantly attenuated AAA formation, suggesting that nonvascular ADAR1 is essential for AAA development. ADAR1 deficiency in hematopoietic cells decreased the prevalence and severity of AAA while inhibited macrophage infiltration and aorta wall inflammation. ADAR1 deletion blocked the classic macrophage activation, diminished NF-κB (nuclear factor kappa B) signaling, and enhanced the expression of a number of anti-inflammatory microRNAs. Mechanistically, ADAR1 interacted with Drosha to promote its degradation, which attenuated Drosha-DGCR8 (DiGeorge syndrome critical region 8) interaction, and consequently inhibited pri- to pre-microRNA processing of microRNAs targeting IKKβ, resulting in an increased IKKβ (inhibitor of nuclear factor kappa-B) expression and enhanced NF-κB signaling. Significantly, ADAR1 was induced in macrophages and interacted with Drosha in human AAA lesions. Reconstitution of ADAR1-deficient, but not the wild type, human monocytes to immunodeficient mice blocked the aneurysm formation in transplanted human arteries.ConclusionsMacrophage ADAR1 promotes aneurysm formation in both mouse and human arteries through a novel mechanism, that is, Drosha protein degradation, which inhibits the processing of microRNAs targeting NF-kB signaling and thus elicits macrophage-mediated vascular inflammation in AAA.

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Macrophage ILF3 promotes abdominal aortic aneurysm by inducing inflammatory imbalance in male mice.

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Macrophage ILF3 promotes abdominal aortic aneurysm by inducing inflammatory imbalance in male mice.

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