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.

项目总结 心血管疾病(CVD)是世界范围内主要的死亡原因，是一种重要的经济 负担。以炎性脂质和免疫细胞积聚为特征的动脉粥样硬化是 心脑血管疾病最常见的潜在原因。在动脉粥样硬化的早期，低密度脂蛋白-胆固醇颗粒 渗入动脉壁的衬里，被修饰(例如，氧化)，并激活炎症通路(例如， NLRP3炎症小体)触发促炎细胞因子的产生。未能消退炎症 动脉壁内会导致斑块的形成。目前的护理标准包括降脂 他汀类药物等药物。然而，即使成功地降脂，仍有一部分患者患有 残留的炎症风险。这些观察导致了几个大规模的临床试验(例如，Cantos和Lo- DoCo2)，靶向全身炎症，治疗动脉粥样硬化性心血管疾病。这些试验表明，目标是- 然而，由于非心血管事件的增加，ING全身炎症减少了不良心血管事件。 在与血管相关的死亡中，目前还没有FDA批准的针对动脉粥样硬化的抗炎疗法。 虽然系统性地针对炎症已经显示出希望，但重要的是确定更具体的靶点和 调节动脉粥样硬化斑块内的炎症，以促进新的治疗方法。的研究。 过去几十年的研究表明，免疫细胞的新陈代谢状态决定了其炎症反应。 和平。因此，我们不是针对全身炎症，而是建议利用 细胞内的炎症。微生物等炎性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，也称为IRG1)显著上调 Acod1)及其下游代谢物衣康酸。除了作为一种抗菌剂，衣康酸还可以控制 免疫激活和诱导免疫耐受通过(1)调节免疫细胞代谢，(2) 抑制晚期NLRP3炎症体活性，以及(3)激活抗炎和抗氧化- 激活转录因子核因子、红系相关因子2和激活转录因子3。 IRG1和衣康酸已经在急性炎症的背景下进行了研究，它们在慢性炎症中的作用 疾病，如动脉粥样硬化，尽管有许多相似的途径，但尚未被探索。 在这项提案中，我将明确IRG1和衣康酸在动脉粥样硬化免疫细胞调节中的作用，特别是 我们已经发现斑块中的三个主要免疫细胞强烈表达IRG1：mono- 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活体小鼠模型来测试 IRG1缺乏是否加重斑块负担和炎症。最后，我将阐明4-OI的用途， 一种用于治疗动脉粥样硬化性心血管疾病的细胞渗透性衣康酸衍生物。如果成功，这将证明 首次研究IRG1和衣康酸在慢性炎症中的作用并确定一种新的治疗方式 动脉粥样硬化性心血管疾病的炎性成分。