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导致了许多治疗选择，但80多年来，心血管疾病一直是美国死亡的主要原因。动脉粥样硬化是最常见的心血管疾病，是一种以动脉内斑块堆积为特征的无菌炎症疾病。据认为，动脉粥样硬化是由低密度脂蛋白(LDL)进入血管系统而开始的，在那里它们随后被氧化(OxLDL)，并对局部组织造成损害。这导致抗原提呈细胞(APC)的募集，包括树突状细胞(DC)和巨噬细胞。在APC激活后，炎症级联反应随之而来，最终导致适应性免疫反应和抗体产生。虽然已知oxLDL抗体的滴度和由此产生的免疫复合体(oxLDL-ICs)与疾病的严重程度相关，但oxLDL-ICs是否在疾病发病机制中发挥作用尚不清楚。ICs通过与DC表面表达的Fc-γ受体(Fc--Rs)相互作用，调节动脉粥样硬化的炎症反应。激活(FcRI/III)和抑制(FcRIIb)Fc受体介导DC中相反的功能，改变促炎DC激活和耐受反应之间的平衡。FcR信号与Toll样受体4(TLR4)相连，TLR4是一种模式识别受体，可以识别游离的oxLDL。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。鉴于在人类动脉粥样硬化斑块中已观察到oxLDLIC和DC表达TLR4，因此，通过TLR4通路的oxLDLIC信号和Fc受体对该通路的调控在疾病的进展中可能是重要的。对巨噬细胞系的研究表明，用oxLDL-ICs治疗后，细胞活性增加。然而，树突状细胞在这一过程中的作用在很大程度上还没有研究，关于体内相关性的报道也很少。鉴于DC具有诱导下游免疫应答的强大能力，了解oxLDL-IC介导的DC激活将填补我们对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，这项研究的长期目标是为动脉粥样硬化领域中这一关键和长期存在的问题提供明确和全面的答案。我们假设，1)oxLDL-ICs增强了TLR4介导的DC炎症反应，导致致动脉粥样硬化的T细胞分化；2)抑制性FcRIIb通过下调DC对oxLDL-ICs的炎症反应来保护动脉粥样硬化。到目前为止，DC特异性的FcRIIb信号在动脉粥样硬化中的作用还没有被研究过。有机会检验这一假说将使我们能够就oxLDL-ICs在心血管疾病中的作用做出“全景”结论。了解已知积累的分子与心血管疾病严重程度呈正相关的病理相关性是至关重要的，这一研究途径对退伍军人具有重要的治疗潜力。在目前超过800万的退伍军人事务部(VA)医疗系统用户中，约有25%的人因动脉粥样硬化而患有缺血性心脏病。这是令人震惊的，特别是考虑到动脉粥样硬化是一种没有治愈方法的疾病，尽管在这个问题上进行了50多年的积极研究。[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同时患有这两种临床并发症，了解动脉粥样硬化的基本机制至关重要。]因此，我们必须继续确定治疗靶点，以便为心血管疾病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.