The role of Immune-responsive gene 1 and itaconate in atherosclerotic disease

免疫反应基因1和衣康酸在动脉粥样硬化疾病中的作用

• 批准号: 10607641
• 负责人: Fazli Kamer Bozal
• 金额: $ 5.27万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10607641
• 关键词: ATF2 gene; Aconitic Acid; Acute; Acute Disease; Agonist; Anti-Inflammatory Agents; Antibodies; Aorta; Area; Arterial Fatty Streak; Arteries; Atherosclerosis; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cell physiology; Cells; Cellular Assay; Cellular Metabolic Process; Cessation of life; Cholesterol; Chromatin; Chronic; Citric Acid Cycle; Classification; Clinical Trials; Data; Development; Economic Burden; Environment; Enzymes; Event; FDA approved; Failure; Gene Expression Regulation; Genes; IL6 gene; Immune; Immune Tolerance; In Vitro; Infection; Infiltration; Inflammasome; Inflammation; Inflammation Mediators; Inflammatory; Interferons; Interleukin-1 beta; Kinetics; LDL Cholesterol Lipoproteins; Lesion; Ligands; Lipids; Lipopolysaccharides; Low-Density Lipoproteins; Macrophage; Measures; Metabolic; Metabolic Pathway; Metabolism; Modality; Modification; Mus; Myeloid Cells; Myocardial Infarction; Necrosis; Pathogenesis; Pathway interactions; Peptide Hydrolases; Permeability; Pharmaceutical Preparations; Production; Reactive Oxygen Species; Regulation; Research; Residual state; Risk; Role; Sampling; Sepsis; Stimulus; Stroke; T-Lymphocyte; Testing; Therapeutic; Therapeutic Effect; Thick; Thrombosis; Time; Toll-like receptors; Transposase; Up-Regulation; Wild Type Mouse; Work; activating transcription factor 3; antimicrobial drug; chronic inflammatory disease; cytokine; extracellular; feeding; immune activation; immunoregulation; in vivo; indexing; inflammatory marker; microbial; monocyte; mouse model; neutrophil; novel; novel therapeutics; nuclear factor-erythroid 2; overexpression; oxidized low density lipoprotein; particle; patient subsets; prevent; recruit; single-cell RNA sequencing; standard of care; systemic inflammatory response; targeted treatment; transcription factor; transcriptome; western diet

PROJECT SUMMARY Cardiovascular disease (CVD) is the leading cause of death worldwide and represents a significant economic burden. Atherosclerosis, which is characterized by a build-up of inflammatory lipids and immune cells, is the most common underlying cause of CVD. Early in the pathogenesis of atherosclerosis, LDL-cholesterol particles infiltrate the lining of the artery wall, are modified (e.g., oxidized), and activate inflammatory pathways (e.g., NLRP3 inflammasome) triggering the production of pro-inflammatory cytokines. A failure to resolve inflammation within the artery wall leads to the development of a plaque. The current standard of care includes lipid-lowering drugs such as statins. However, even with successful lipid-lowering, there remains a subset of patients with residual inflammatory risk. These observations led to several large-scale clinical trials (e.g., CANTOS and Lo- DoCo2) that targeted systemic inflammation to treat atherosclerotic CVD. These trials demonstrated that target- ing systemic inflammation reduces adverse cardiovascular events, however, due to an increase in non-cardio- vascular-related deaths, there are currently no FDA-approved anti-inflammatory therapies for atherosclerosis. While targeting inflammation systemically has shown promise, it is important to identify more specific targets and regulators of inflammation within the atherosclerotic plaque to leverage into novel therapies. Research over the past few decades has established that the metabolic state of the immune cell determines its inflammatory ca- pacity. As such, rather than targeting systemic inflammation, we propose to leverage the metabolic regulators of inflammation within the cell. Studies of macrophages stimulated with inflammatory mediators including microbial ligands and cytokines have revealed significant upregulation of the gene Immune-responsive gene 1 (Irg1, also Acod1) and its downstream metabolite itaconate. In addition to being an anti-microbial agent, itaconate controls immune activation and elicits immunological tolerance through (1) regulation of immune cell metabolism, (2) inhibition of late-stage NLRP3 inflammasome activity, and (3) activation of the anti-inflammatory and anti-oxida- tive transcription factors Nuclear factor erythroid 2-related factor 2 and Activating transcription factor 3. While Irg1 and itaconate have been studied in the context of acute inflammation, their role in chronic inflammatory disease, such as atherosclerosis, has not been explored despite sharing many similar pathways. In this proposal, I will define the role of Irg1 and itaconate on immune cell regulation in atherosclerosis, specifi- cally the effects on three major immune cells within the plaque we have found to robustly express Irg1: mono- cytes, macrophages, and neutrophils. Additionally, I will utilize in vivo mouse models of atherosclerosis to test whether IRG1 deficiency exacerbates plaque burden and inflammation. Finally, I will elucidate the utility of 4-OI, a cell-permeable itaconate derivative as a treatment in atherosclerotic CVD. If successful, this will demonstrate for the first time the role of Irg1 and itaconate in chronic inflammation and identify a novel treatment modality for the inflammatory component of atherosclerotic CVD.

项目概要 心血管疾病（CVD）是全世界死亡的主要原因，并且代表着重要的经济 负担。动脉粥样硬化的特征是炎症脂质和免疫细胞的积聚，是 CVD 最常见的根本原因。在动脉粥样硬化发病机制的早期，低密度脂蛋白胆固醇颗粒 渗透动脉壁内壁，被修饰（例如氧化）并激活炎症途径（例如， NLRP3 炎症小体）触发促炎细胞因子的产生。未能解决炎症 动脉壁内导致斑块的形成。目前的护理标准包括降脂 他汀类药物等药物。然而，即使成功降脂，仍有一小部分患者患有以下疾病： 残留炎症风险。这些观察导致了几项大规模的临床试验（例如，CANTOS 和 Lo- DoCo2）针对全身炎症来治疗动脉粥样硬化性心血管疾病。这些试验表明，目标 然而，由于非心血管事件的增加，全身性炎症可减少不良心血管事件。 与血管相关的死亡，目前尚无 FDA 批准的动脉粥样硬化抗炎疗法。 虽然系统性靶向炎症已显示出希望，但重要的是确定更具体的目标和 动脉粥样硬化斑块内炎症的调节因子可用于新疗法。研究遍及 过去几十年已经确定免疫细胞的代谢状态决定其炎症反应 节奏。因此，我们建议利用代谢调节剂，而不是针对全身炎症 细胞内的炎症。用包括微生物在内的炎症介质刺激巨噬细胞的研究 配体和细胞因子显示免疫反应基因 1（Irg1，也 Acod1) 及其下游代谢物衣康酸。除了作为抗微生物剂外，衣康酸还可以控制 通过 (1) 调节免疫细胞代谢，(2) 激活免疫并引发免疫耐受 抑制晚期 NLRP3 炎症小体活性，以及​​ (3) 激活抗炎和抗氧化活性 活性转录因子 核因子红细胞 2 相关因子 2 和激活转录因子 3。 Irg1 和衣康酸已在急性炎症的背景下进行了研究，以及它们在慢性炎症中的作用 尽管有许多相似的途径，但动脉粥样硬化等疾病尚未得到探索。 在这个提案中，我将定义 Irg1 和衣康酸在动脉粥样硬化中免疫细胞调节中的作用，具体来说： 特别是对斑块内三种主要免疫细胞的影响，我们发现它们强烈表达 Irg1：单- 细胞、巨噬细胞和中性粒细胞。此外，我将利用动脉粥样硬化的体内小鼠模型来测试 IRG1 缺乏是否会加剧斑块负担和炎症。最后，我将阐明 4-OI 的用途， 一种细胞渗透性衣康酸酯衍生物，用于治疗动脉粥样硬化性 CVD。如果成功的话，这将表明 首次研究了 Irg1 和衣康酸在慢性炎症中的作用，并确定了一种新的治疗方式 动脉粥样硬化性CVD的炎症成分。