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和死于心血管疾病（CVD）的风险增加，包括心肌梗死和中风。介导皮肤病和CVD的炎症级联反应具有惊人的相似性，包括抗原提呈细胞和巨噬细胞的活化，Th1、Th17和调节性T细胞的参与，以及IL-12p40、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不确定。为了确定远程炎症是否会引发共病并发症，如心血管疾病，我们设计了一个四环素抑制的慢性炎症小鼠模型，通过异位表达血管生成素受体，Tie2专门向角质形成细胞（KC）表达。KC-Tie2小鼠出现持续的皮肤炎症，其特征是真皮白细胞浸润和促炎细胞因子增加。目前最重要的是，在野生型背景下，约33%的KC-Tie2小鼠自发形成动脉粥样硬化斑块，并且促动脉粥样硬化CD11b+Ly-6Chi单核细胞水平升高。此外，与对照组相比，KC-Tie2动物闭塞血栓形成的时间显着缩短。在没有任何标准的心血管疾病危险因素（如高脂血症、高血压、糖尿病）的情况下，研究慢性皮肤局限性炎症并发心血管疾病的模型，为确定长期非血管炎症介导的促动脉粥样硬化和促血栓形成的细胞机制提供了一个创新的临床前机会。我们假设慢性炎症增加循环CD11b+Ly-6Chi单核细胞并促进动脉粥样硬化血栓形成。结合小鼠分子遗传学，利用小分子抑制剂和功能阻断抗体的治疗靶向策略，再加上骨髓和皮肤移植方法，我们建议确定慢性皮肤特异性炎症引发的促动脉粥样硬化和促血栓形成的细胞机制。总之，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。这些研究的结果将为慢性炎症性疾病（包括类风湿关节炎、结肠炎、牙龈疾病、牛皮癣和狼疮）相关的CVD合并症的病因学和新疗法的发展提供见解。

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.