Macrophage-specific IEX-1 – A Novel Mechanism in the Pathogenesis of Atherosclerosis

巨噬细胞特异性IEX-1--动脉粥样硬化发病的新机制 动脉粥样硬化是一种慢性炎症性疾病，其特征是脂质在动脉壁中积聚。 它是美国发病率和死亡率的主要原因。几种免疫细胞参与了该病的发生。 动脉粥样硬化；然而，巨噬细胞在疾病的所有阶段都发挥着中心作用。新出现的证据 提示巨噬细胞的数量和表型都影响着巨噬细胞的发生和发展。 动脉粥样硬化病变。在动脉粥样硬化斑块中发现了几个巨噬细胞亚群， 包括经典激活(CAMS)、交替激活(AAM)和基于其不同基因的Mox 表情。具有CAMS样特征的巨噬细胞在动脉粥样硬化的启动中起着至关重要的作用 渗入内皮下间隙，促进炎症。它们吞噬脂质，成为泡沫细胞，以 形成斑块。相比之下，AAM样巨噬细胞富含退化的斑块。它们抑制了 炎症，泡沫细胞形成减少。然而，善意因素的同一性对 对巨噬细胞表型的调控仍知之甚少。其结果是，缺乏有效的 抑制巨噬细胞促动脉粥样硬化表型以减少动脉粥样硬化的策略。IEX-1是一种压力- 在巨噬细胞中高表达的可诱导基因。我们的初步调查显示IEX-1是 对于动脉粥样硬化的发展是必不可少的，并且它的缺陷保护小鼠免受动脉粥样硬化的影响 影响胆固醇新陈代谢。有趣的是，IEX-1缺陷逆转了巨噬细胞的表型 巨噬细胞从CAMS向AAM样状态渗入，对巨噬细胞的渗入影响不大。AAM- 偏振先于动脉粥样硬化斑块的形成。在目前的提案中，我们将 提出巨噬细胞中IEX-1活性是动脉粥样硬化形成所必需的假说。为了解决这个问题，我们 建议使用一种新的小鼠模型，在该模型中，IEX-1将在ApoE-1上选择性地从巨噬细胞中删除 缺乏背景。我们将研究其对动脉粥样硬化斑块形成、主动脉巨噬细胞的影响。 表型和炎症状态。此外，为了从机制上深入了解IEX-1如何对 我们计划研究细胞凋亡和糖酵解在巨噬细胞极化和泡沫中的作用。 细胞形成，斑块形成的中心步骤。我们将采用几种药理学方法来 改变IEX-1的表达或糖酵解并评价其对巨噬细胞表型和泡沫细胞的影响 制作。总之，这些研究将促进我们对巨噬细胞表型如何调节的理解。 动脉硬化。这一结果可能有助于开发有前景的治疗或诊断脂质驱动的方法 炎症状态，如动脉粥样硬化、糖尿病和肥胖。

Macrophage-specific IEX-1 – A Novel Mechanism in the Pathogenesis of Atherosclerosis Atherosclerosis is a chronic inflammatory disease characterized by the accumulation of lipids in the artery wall. It is the leading cause of morbidity and mortality in the US. Several immune cells are involved in genesis of atherosclerosis; however, macrophages play a central role in all stages of the disease. Emerging evidence suggests that both the quantity and phenotype of macrophages influence the inception and progression of atherosclerotic lesions. Several macrophages subsets have been identified in atherosclerotic plaques, including classically-activated (CAMs), alternatively-activated (AAMs), and Mox based on their distinct gene expression. Macrophages with CAMs-like characteristics play a crucial role in initiation of atherosclerosis by infiltrating in sub-endothelial space and promoting inflammation. They engulf lipids and become foam cell to form plaque. In contrast, AAMs-like macrophages are enriched in regressing plaques. They inhibit inflammation and exhibit reduced foam cell formation. However, the identity of bona fide factors that critically regulate macrophage phenotype remain poorly understood. As a result, there is a dearth of the effective strategies to inhibit pro-atherogenic phenotype of macrophages to reduce atherosclerosis. IEX-1 is a stress- inducible gene that is highly expressed in macrophages. Our preliminary investigation revealed that IEX-1 is essential for atherosclerosis development and that its deficiency protected mice against atherosclerosis without impacting cholesterol metabolism. Interestingly, IEX-1 deficiency reversed the phenotype of macrophages infiltrated in aorta from CAMs to a AAMs-like state, with only little effect on macrophage infiltration. AAMs- biased polarization preceded the development of atherosclerotic plaque. In the current proposal we will address the hypothesis that IEX-1 activity in macrophages is required for atherogenesis. To address this, we propose to use a novel mouse model in which IEX-1 will be selectively deleted from macrophages on ApoE- deficiency background. We will study its impact on atherosclerotic plaque formation, aortic macrophage phenotype, and inflammatory status. Furthermore, to gain a mechanistic insight into how IEX-1 contributes to atherosclerosis, we plan to investigate a role of apoptosis and glycolysis in macrophage polarization and foam cell formation, the central step in plaque formation. We will employ several pharmacological approaches to alter IEX-1 expression or glycolysis and evaluate its impact on macrophage phenotype and foam cell production. Together, these studies will advance our understanding of how macrophage phenotype regulates atherosclerosis. The results may help develop promising therapeutic or diagnostic approaches for lipid-driven inflammatory conditions such as atherosclerosis, diabetes, and obesity.