Remote Inflammation and Atherothrombosis

描述（由申请人提供）：回顾性流行病学研究表明，慢性炎症性皮肤病患者发生心血管疾病（CVD）和死亡的风险增加，包括心肌梗死和卒中。介导皮肤病和CVD的炎症级联反应具有惊人的相似性，包括抗原呈递细胞和巨噬细胞的活化，Th 1，Th 17和调节性T细胞的参与，以及IL-12 p40，IL-17和TNF的关键作用。远端炎症是否有能力启动动脉粥样硬化和/或血栓形成的发病机制尚未确定。 为了确定远程炎症是否可以引发共病并发症，如CVD，我们通过异位表达血管生成素受体Tie 2专门到角质形成细胞（KC）来设计慢性炎症的四环素抑制性二元小鼠模型。KC-Tie 2小鼠发生以真皮浸润白细胞和促炎细胞因子增加为特征的持续性皮肤炎症。对于目前的提议最重要的是，野生型背景下约33%的KC-Tie 2小鼠自发地发展动脉粥样硬化斑块，并且具有升高的促动脉粥样硬化CD 11b +Ly-6Chi单核细胞水平。此外，与对照同窝仔相比，KC-Tie 2动物中闭塞性血栓形成的时间显著缩短。 研究在不存在任何标准CVD风险因素（例如高脂血症、高血压、糖尿病）的情况下发展CVD共病的慢性皮肤局限性炎症模型的机会为鉴定由长期非血管炎症介导的促动脉粥样硬化和促血栓形成细胞机制提供了创新的临床前机会。我们假设慢性炎症增加循环中的CD 11b +Ly-6Chi单核细胞并促进动脉粥样硬化血栓形成。使用小鼠分子遗传学的组合，利用小分子抑制剂和功能阻断抗体的治疗靶向策略，结合骨髓和皮肤移植方法，我们提出鉴定由慢性皮肤特异性炎症引起的促动脉粥样硬化和促血栓形成的细胞机制。 总的来说，我们的研究将阐明慢性远端炎症介导的动脉粥样硬化血栓形成的细胞基础。这些研究的结果将提供针对与慢性炎症性疾病（包括类风湿性关节炎、结肠炎、牙龈疾病、银屑病和狼疮）相关的CVD共病的病因学和新型疗法开发的见解。 公共卫生相关性：缺血性心脏病、脑血管疾病、外周动脉疾病的患病率增加，并且患有慢性炎性疾病（例如类风湿性关节炎（RA）、结肠炎、牙龈疾病、牛皮癣和狼疮）的个体的死亡风险增加。了解远程炎症和心血管疾病的细胞和分子机制将提供新的知识，为什么这种关系存在，更重要的是将提供新的治疗开发策略，针对与慢性炎症相关的心血管并发症的治疗。

DESCRIPTION (provided by applicant): Retrospective epidemiological studies have demonstrated that patients with chronic inflammatory skin disease have an increased risk for developing and dying of cardiovascular disease (CVD), including myocardial infarction and stroke. Inflammatory cascades that mediate skin disease and CVD have striking similarities including activation of antigen presenting cells and macrophages, involvement of Th1, Th17 and regulatory T cells, and critical roles for IL-12p40, IL-17 and TNF. Whether remote inflammation has the capacity to initiate atherosclerosis and/or thrombosis pathogenesis is as yet undetermined. To determine if remote inflammation can instigate co-morbid complications such as CVD, we engineered a tetracycline-repressible binary mouse model of chronic inflammation by ectopically expressing the angiopoeitin receptor, Tie2 exclusively to keratinocytes (KC). The KC-Tie2 mouse develops unremitting skin inflammation characterized by dermal infiltrating leukocytes and increased proinflammatory cytokines. Most significant for the current proposal is ~33% of KC-Tie2 mice on a wild type background spontaneously develop atherosclerotic plaque and have elevated levels of pro-atherogenic CD11b+Ly-6Chi monocytes. Moreover, the time to occlusive thrombus formation in KC-Tie2 animals is significantly shortened compared to control littermates. The opportunity to study a model of chronic skin-confined inflammation that develops CVD co-morbidities in the absence of any of the standard CVD risk factors (e.g. hyperlipidemia, hypertension, diabetes) provides an innovative preclinical opportunity to identify pro-atherogenic and pro-thrombotic cellular mechanism(s) mediated by long term non-vascular inflammation. We hypothesize that chronic inflammation increases circulating CD11b+Ly-6Chi monocytes and promotes atherothrombosis. Using a combination of mouse molecular genetics, therapeutic targeting strategies utilizing small molecule inhibitors and function blocking antibodies, coupled with bone marrow and skin transplant approaches we propose to identify pro-atherogenic and pro-thrombotic cellular mechanism(s) elicited by chronic skin-specific inflammation. Collectively, our studies will elucidate the cellular basis underlying chronic remot inflammation-mediated atherothrombosis. The results of these studies will provide insight into the etiology and development of novel therapies directed towards CVD co-morbidities associated with chronic inflammatory diseases including rheumatoid arthritis, colitis, gum disease, psoriasis and lupus. PUBLIC HEALTH RELEVANCE: There is an increased prevalence of ischemic heart disease, cerebrovascular disease, peripheral artery disease and an increased risk of death in individuals suffering from chronic inflammatory diseases, such as rheumatoid arthritis (RA), colitis, gum disease, psoriasis and lupus. Understanding the cellular and molecular mechanisms linking remote inflammation and cardiovascular disease will provide new knowledge as to why this relationship exists and more importantly will provide novel therapeutic development strategies directed at the treatment of the cardiovascular co-morbidities associated with chronic inflammation.