oxLDL immune complex-mediated modulation of atherosclerosis

 描述（由申请人提供）： 心血管疾病（CVD）每年导致大约100万美国人死亡。尽管现代医学的进步带来了许多治疗选择，但CVD仍然是美国80多年来死亡的主要原因。动脉粥样硬化是最常见的CVD形式，是一种无菌性炎症疾病，其特征在于动脉中斑块的积累。据认为，动脉粥样硬化是通过低密度脂蛋白（LDL）进入血管系统中并在其中被隔离而引发的，在血管系统中它们随后被氧化（oxLDL）并对局部组织造成损伤。这导致包括树突状细胞（DC）和巨噬细胞的抗原呈递细胞（APC）的募集。APC激活后，炎症级联反应增强，最终导致适应性免疫应答和抗体产生。虽然已知oxLDL抗体和产生的免疫复合物（oxLDL-IC）的滴度与疾病严重程度相关，但尚不清楚oxLDL-IC是否在疾病发病机制中发挥作用。IC可以通过与DC表面表达的Fc γ受体（Fc γ R）相互作用来调节动脉粥样硬化中的炎症。激活性（Fc ε RI/III）和抑制性（Fc ε RIIb）Fc ε R介导DC中相反的功能，改变促炎性DC激活和致耐受性应答之间的平衡。Fc γ R信号传导与Toll样受体-4（TLR-4）相关，TLR-4是一种可识别游离oxLDL的模式识别受体。此外，我们使用TLR-4抑制剂的初步数据表明，oxLDL-IC能够通过该受体发出信号。鉴于在人动脉粥样硬化斑块中观察到oxLDL-IC和表达TLR-4的DC，通过TLR-4途径的oxLDL-IC信号传导和Fc受体对该途径的调节在疾病进展中可能是重要的。在巨噬细胞系中的研究显示，用oxLDL-IC处理后细胞活化增加。然而，DC在这一过程中的作用在很大程度上是未研究的，并且缺乏关于体内相关性的报道。鉴于DC引发下游免疫应答的强大能力，了解oxLDL-IC介导的DC活化将填补我们对CVD发病机制的认识空白，并为治疗干预提供新的途径。使用体外和体内模型，本研究的长期目标是为动脉粥样硬化领域的这一关键和长期存在的问题提供一个明确而全面的答案。我们假设：1）oxLDL-1C增强TLR-4介导的DC炎症反应，导致致动脉粥样硬化性T细胞分化; 2）抑制性Fc γ RIIb通过下调DC对oxLDL-1C的炎症反应来预防动脉粥样硬化。到目前为止，尚未研究DC特异性Fc γ RIIb信号传导在动脉粥样硬化中的作用。有机会检验这一假设将使我们能够就oxLDL-IC在CVD中的作用得出“大局”结论。了解已知积累的分子的病理相关性并与CVD严重程度呈正相关是至关重要的，这种研究途径对退伍军人具有重要的治疗潜力。目前超过800万退伍军人事务部（VA）医疗系统用户中约有25%因动脉粥样硬化而患有缺血性心脏病。这是令人担忧的，特别是考虑到动脉粥样硬化是一种无法治愈的疾病，尽管对该主题进行了50多年的积极研究。[In此外，动脉粥样硬化的风险增加与创伤后应激障碍和导致截肢的损伤有关。鉴于越来越多的退伍军人患有这两种临床并发症，需要了解动脉粥样硬化的基本机制是至关重要的。因此，我们必须继续确定治疗靶点，以便为CVD的尖端治疗提供基础。

 DESCRIPTION (provided by applicant): Cardiovascular disease (CVD) accounts for the deaths of approximately 1 million Americans annually. Despite advances in modern medicine that have led to numerous treatment options, CVD has remained the leading cause of mortality in the US for over 80 years. Atherosclerosis, the most common form of CVD, is a disease of sterile inflammation characterized by accumulation of plaque in the arteries. It is thought that atherosclerosis is initiated by entry an sequestration of low density lipoproteins (LDL) in the vasculature where they subsequently become oxidized (oxLDL) and cause damage to local tissue. This results in the recruitment of antigen presenting cells (APCs) including dendritic cells (DCs) and macrophages. Following APC activation, an inflammatory cascade ensues, ultimately leading to an adaptive immune response and antibody production. While titers of antibodies to oxLDL and the resulting immune complexes (oxLDL-ICs) are known to correlate with disease severity, it is unknown if oxLDL-ICs play a role in disease pathogenesis. ICs can regulate inflammation in atherosclerosis by interacting with Fc gamma receptors (FcRs) expressed on the surface of DCs. Activating (FcRI/III) and inhibitory (FcRIIb) FcRs mediate opposing functions in DCs, shifting the balance between pro-inflammatory DC activation and tolerogenic responses. FcR signaling has been linked to Toll like receptor-4 (TLR-4), a pattern recognition receptor that can recognize free oxLDL. Furthermore, our preliminary data using a TLR-4 inhibitor suggest that oxLDL-ICs are able to signal through this receptor. Given that both oxLDL-ICs and DCs expressing TLR-4 have been observed in human atherosclerotic plaques, it is likely that oxLDL-IC signaling via the TLR-4 pathway and modulation of this pathway by FcRs are important in disease progression. Studies in macrophage cell lines have shown increased cellular activation following treatment with oxLDL-ICs. However, the role of DCs in this process is largely unstudied, and reports regarding the in vivo relevance are lacking. Given the potent ability of DCs to elicit a downstream immune response, understanding oxLDL-IC-mediated DC activation will fill a gap in our knowledge of CVD pathogenesis and provide new avenues for therapeutic intervention. Using both in vitro and in vivo models, the long term goal of this study is to provide a clear and comprehensive answer to this critical and long-standing question in the field of atherosclerosis. We hypothesize that 1) oxLDL-ICs augment TLR-4-mediated DC inflammatory responses leading to proatherogenic T cell differentiation and 2) the inhibitory FcRIIb protects against atherosclerosis by down-regulating DC inflammatory responses to oxLDL-ICs. To date, the effects of DC-specific FcRIIb signaling in atherosclerosis have not been examined. Being afforded the opportunity to test this hypothesis will allow us to make "big picture" conclusions regarding the role of oxLDL-ICs in CVD. Understanding the pathological relevance of molecules known to accumulate and positively correlate with CVD severity is vital, and this avenue of research has important therapeutic potential for Veterans. Approximately 25% of the more than 8 million current Veterans Affairs (VA) medical system users suffer from ischemic heart disease due to atherosclerosis. This is alarming, especially considering that atherosclerosis is a disease for which no cure exists, despite over 50 years of active research on the subject. [In addition, increased risk for atherosclerosis is associated with PTSD and injuries resulting in amputation. Given the growing number of Veterans suffering from both of these clinical complications the need to understand basic mechanisms of atherosclerosis is crucial.] Therefore, it is imperative that we continue to identify therapeutic targets in order to provide a basis for cutting edge treatments for CVD.