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.

项目摘要 心血管疾病（CVD）是全球死亡的主要原因，代表着一个重要的经济问题。 负担以炎症脂质和免疫细胞的积聚为特征的动脉粥样硬化， 最常见的CVD潜在原因。在动脉粥样硬化发病的早期，LDL-胆固醇颗粒 渗透动脉壁的内层，被修饰（例如，氧化），并激活炎症途径（例如， NLRP 3炎性体），触发促炎细胞因子的产生。未能解决炎症 导致斑块的形成。目前的标准治疗包括降脂 药物如Statins。然而，即使成功降脂，仍有一部分患者 残余炎症风险。这些观察结果导致了几项大规模的临床试验（例如，坎托斯和洛- DoCo 2），其靶向全身炎症以治疗动脉粥样硬化CVD。这些试验表明，目标- 全身性炎症减少了不良心血管事件，然而，由于非心血管事件的增加， 血管相关的死亡，目前没有FDA批准的用于动脉粥样硬化的抗炎疗法。 虽然全身靶向炎症已经显示出希望，但重要的是要确定更特异的靶标， 动脉粥样硬化斑块内的炎症调节剂，以利用到新的治疗。研究在 过去的几十年已经证实，免疫细胞的代谢状态决定了其炎症性疾病， 和平。因此，我们建议利用代谢调节剂，而不是针对全身性炎症， 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 配体和细胞因子已经揭示了基因免疫应答基因1（Irg 1，也 Acod 1）及其下游代谢产物衣康酸盐。除了作为一种抗微生物剂，衣康酸盐控制 通过（1）调节免疫细胞代谢，（2） 抑制晚期NLRP 3炎性体活性，和（3）激活抗炎和抗氧化酶活性。 激活转录因子核因子红细胞2相关因子2和激活转录因子3。而 已经在急性炎症的背景下研究了irg 1和衣康酸盐，它们在慢性炎症中的作用， 尽管有许多相似的途径，但诸如动脉粥样硬化的疾病尚未被探索。 在这个提议中，我将定义Irg 1和衣康酸盐在动脉粥样硬化中对免疫细胞调节的作用，具体来说， 我们已经发现斑块内的三种主要免疫细胞强烈表达Irg 1： 细胞、巨噬细胞和嗜中性粒细胞。此外，我将利用动脉粥样硬化的体内小鼠模型来测试 IRG 1缺乏是否会加重斑块负荷和炎症。最后，我将阐明4-OI的效用， 一种用于治疗动脉粥样硬化性CVD的细胞可渗透衣康酸酯衍生物。如果成功，这将证明 首次研究了Irg 1和衣康酸盐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CVD的炎症成分。