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

系统性红斑狼疮(SLE)是一种慢性炎症性自身免疫性疾病，与 加速动脉粥样硬化。系统性红斑狼疮合并心肌梗死(MI)的总体风险是 在35-44岁的女性中，患病风险是普通人群的50倍。为什么SLE或其他疾病患者 自身免疫性疾病动脉粥样硬化的风险增加尚不清楚，需要生物标志物来 找出心血管不良事件风险较高的人群。炎症是肺炎的一个重要组成部分 动脉粥样硬化的形成过程。最近的研究有力地表明了促炎细胞因子IL-1β在糖尿病中的中心作用 动脉粥样硬化，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。我们 已经确定免疫危险信号通过产生反应性而导致线粒体功能障碍 氧气物种。由此产生的氧化损伤的线粒体dna(Mtdna)被释放到细胞质中。 在那里它与NLRP3炎症小体结合并激活，炎症小体是产生活性IL-1β的机制。我们 研究表明，8-氧鸟嘌呤-DNA糖基酶1(OGG1)是一种参与修复氧化的mtDNA的酶， 防止NLRP3炎症小体激活和IL-1β的产生。重要的是，阿迪提实验室中未发表的工作 表明OGG1基因缺陷的小鼠更容易患上动脉粥样硬化，强调 这种酶的保护作用。众所周知，系统性红斑狼疮患者会产生线粒体氧化DNA 破坏和积累非常高浓度的氧化mtDNA产物，进而放大 发炎。此外，OGG1中的失活多态与糖尿病的发生有关。 系统性红斑狼疮合并肾炎。鉴于这一背景，我们假设氧化DNA损伤导致SLE- 与动脉粥样硬化相关，OGG1是保护性的，因此是新的治疗靶点 干预。为了验证这一假设，我们将采取双管齐下的方法，使用SLE小鼠模型 高脂血症及其来源免疫细胞中NLRP3和OGG1活性和功能的体外分析 有动脉粥样硬化的SLE患者与无动脉粥样硬化的SLE患者比较。我们提出了两个具体目标：目标1-调查 线粒体OGG1作为预防系统性红斑狼疮相关动脉粥样硬化的新治疗靶点的作用目标2- 线粒体DNA在SLE动脉粥样硬化形成中NLRP3激活中的作用及OGG1在限制中的作用 伴或不伴动脉粥样硬化的SLE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OGG1或通过调节OGG1表达的新型microRNA来实现 评估靶向OGG1作为SLE相关动脉粥样硬化潜在治疗方法的有效性。 这些研究的完成将大大加强我们目前对致病机制的了解。 在系统性红斑狼疮期间加速动脉粥样硬化的研究，并发现这种非常重要的疾病的新治疗靶点。

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 Importantly, unpublished work in the Arditi lab demonstrates that mice deficient in OGG1 are more prone to develop atherosclerosis, emphasizing the protective effect of this enzyme.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.