Atherosclerosis in SLE - OGG-1 as a novel target for therapeutic intervention

SLE 中的动脉粥样硬化 - OGG-1 作为治疗干预的新靶点

• 批准号: 9306766
• 负责人: Moshe Arditi
• 金额: $ 26.25万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9306766
• 关键词: 8-Oxoguanine DNA Glycosylase; Address; Adopted; Atherosclerosis; Attenuated; Autoimmune Diseases; Binding; Binding Sites; Biological Markers; Cardiovascular system; Cells; Chronic; Cytoplasm; DNA Damage; DNA glycosylase; Data; Development; Disease; Enzymes; Event; General Population; Generations; Genetic Polymorphism; Human; Hyperlipidemia; Immune; Immunologics; Inflammasome; Inflammation; Inflammatory; Interleukin-1 beta; Life; Messenger RNA; MicroRNAs; Mitochondria; Mitochondrial DNA; Mus; Myocardial Infarction; Nephritis; Oxides; Pathogenicity; Patients; Pristane; Process; Production; Reactive Oxygen Species; Risk; Role; Signal Transduction; System; Systemic Lupus Erythematosus; Testing; Therapeutic; Therapeutic Intervention; United States; Woman; aged; atherogenesis; cytokine; effective therapy; high risk; mitochondrial dysfunction; monocyte; mortality; mouse model; new therapeutic target; novel; novel therapeutics; oxidative DNA damage; oxidative damage; prevent; protective effect; repaired; therapeutic target; translational approach; unpublished works

Systemic Lupus Erythematosus (SLE) is a chronic inflammatory autoimmune disease, which is associated with accelerated atherosclerosis. The overall risk of myocardial infarction (MI) with SLE is 10-fold higher than in the general population and a 50-fold higher risk in women aged 35-44 years. Why patients with SLE or other autoimmune diseases are at increased risk of atherosclerosis remains unclear, and biomarkers are needed to identify those at higher risk of adverse cardiovascular events. Inflammation is a key component of the atherogenic process. Recent studies strongly indicate a central role for the proinflammatory cytokine IL-1β in atherosclerosis, although the mechanism by which IL-1β is activated during atherogenesis is unknown. We have determined that immunologic danger signals induce mitochondrial dysfunction with generation of reactive oxygen species. The resulting oxidatively damaged mitochondrial DNA (mtDNA) is released into the cytoplasm where it binds to and activates the NLRP3 inflammasome, the machinery by which active IL-1β is made. We have shown that 8-oxoguanine-DNA glycosylase 1 (OGG1), an enzyme involved in repairing oxidized mtDNA, prevents NLRP3 inflammasome activation and IL-1β production. Importantly, unpublished work in the Arditi lab demonstrates that mice deficient in OGG1 are more prone to develop atherosclerosis, emphasizing the protective effect of this enzyme. It is well known that SLE patients develop mitochondrial oxidative DNA damage and accumulate very high concentrations of oxidative mtDNA products that in turn amplify inflammation. Moreover, inactivating polymorphisms in OGG1 have been associated with the development of nephritis in SLE. Given this background, we hypothesize that oxidative DNA damage leads to SLE- associated atherogenesis and that OGG1 is protective and hence a novel target for therapeutic intervention. To test this hypothesis, we will adopt a two-pronged approach, using SLE mouse models with hyperlipidemia, and ex vivo analysis of NLRP3 and OGG1 activity and function in immune cells derived from SLE patients with atherosclerosis vs. those without. We propose two Specific Aims: Aim 1-To investigate the role of mitochondrial OGG1 as a novel therapeutic target to prevent SLE-associated atherogenesis. Aim 2 – To determine the role of mtDNA in NLRP3 activation in SLE atherogenesis and the role of OGG1 in limiting mtDNA damage in immune cells from SLE patients with or without atherosclerosis. We will manipulate these systems via mitochondrial targeting of OGG1 or via novel microRNA that regulates OGG1 expression so as to evaluate the utility of targeting OGG1 as a potential therapeutic approach in SLE-associated atherosclerosis. Completion of these studies will significantly enhance our current understanding the pathogenic mechanisms of accelerated atherogenesis during SLE and uncover new therapeutic targets for this very important disease.

系统性红斑狼疮（SLE）是一种慢性炎症性自身免疫性疾病，其与 加速动脉粥样硬化SLE患者发生心肌梗死（MI）的总体风险是正常对照组的10倍。 一般人群中，35-44岁的妇女的风险高出50倍。为什么SLE患者或其他 自身免疫性疾病增加动脉粥样硬化的风险仍不清楚，需要生物标志物来 确定那些有较高风险的不良心血管事件。炎症是一个关键组成部分， 动脉粥样硬化过程最近的研究强烈表明，促炎细胞因子IL-1β在 尽管IL-1β在动脉粥样硬化形成过程中被激活的机制尚不清楚，但IL-1β在动脉粥样硬化形成过程中被激活的机制仍是未知的。我们 已经确定免疫危险信号诱导线粒体功能障碍， 氧物种。由此产生的氧化损伤的线粒体DNA（mtDNA）被释放到细胞质中 在那里它结合并激活NLRP 3炎性体，这是产生活性IL-1β的机制。我们 已经表明8-氧代鸟嘌呤-DNA糖基化酶1（OGG 1），一种参与修复氧化mtDNA的酶， 阻止NLRP 3炎性体活化和IL-1β产生。重要的是，Arditi实验室未发表的工作 表明OGG 1缺陷的小鼠更容易发生动脉粥样硬化，强调了 这种酶的保护作用。众所周知，SLE患者的线粒体氧化DNA 损伤并积累非常高浓度的线粒体DNA氧化产物， 炎症此外，OGG 1的失活多态性与以下疾病的发生有关： 狼疮性肾炎在此背景下，我们假设氧化性DNA损伤导致SLE- 相关的动脉粥样硬化形成，OGG 1是保护性的，因此是治疗动脉粥样硬化的新靶点。 干预为了验证这一假设，我们将采用双管齐下的方法，使用SLE小鼠模型， 高脂血症的免疫细胞中的NLRP 3和OGG 1活性和功能的体外分析，以及来自 有动脉粥样硬化的SLE患者与无动脉粥样硬化的SLE患者。我们提出了两个具体目标：目标1-调查 线粒体OGG 1作为预防SLE相关动脉粥样硬化形成的新治疗靶点的作用。目标2 - 确定mtDNA在SLE动脉粥样硬化形成中NLRP 3激活中的作用以及OGG 1在限制SLE动脉粥样硬化形成中的作用。 SLE伴或不伴动脉粥样硬化患者免疫细胞线粒体DNA损伤我们将操纵这些 系统通过线粒体靶向OGG 1或通过调节OGG 1表达的新型microRNA， 评估靶向OGG 1作为SLE相关动脉粥样硬化的潜在治疗方法的效用。 这些研究的完成将大大提高我们目前对致病机制的理解 并为这一重要疾病发现新的治疗靶点。

项目成果

Oxidative DNA Damage Accelerates Skin Inflammation in Pristane-Induced Lupus Model.

• DOI: 10.3389/fimmu.2020.554725
• 发表时间: 2020
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Tumurkhuu G;Chen S;Montano EN;Ercan Laguna D;De Los Santos G;Yu JM;Lane M;Yamashita M;Markman JL;Blanco LP;Kaplan MJ;Shimada K;Crother TR;Ishimori M;Wallace DJ;Jefferies CA;Arditi M
• 通讯作者: Arditi M