Role of Fc gamma receptors in atherosclerosis

描述(申请人提供)：动脉粥样硬化是血管内皮细胞的慢性炎症过程，导致心血管疾病。氧化形式的低密度脂蛋白(OxLDL)的产生和巨噬细胞对其的摄取是动脉粥样硬化的早期事件。氧化低密度脂蛋白还可诱导自身免疫反应，在患者和动物模型的动脉粥样硬化病变中可检测到针对氧化低密度脂蛋白的抗体(IgG)和氧化低密度脂蛋白免疫复合物(oxLDL-IC)。在人类和高脂血症小鼠模型中，oxLDL自身抗体的滴度与动脉粥样硬化的进展相关。因此，oxLDL-IC可能参与了导致动脉粥样硬化发生和发展的炎症过程。我们已经证明，体外培养的人单核细胞与oxLDL-IC包被的内皮细胞黏附，并释放炎性细胞因子。这种相互作用是由一组称为Fc？r受体的细胞受体介导的，Fc？R与免疫复合体结合，在涉及自身抗体的慢性炎症性疾病中IC介导的组织损伤中发挥重要作用。OxLDL-IC与含有激活基序的Fc？Rs相互作用可启动炎症反应，而与含有抑制性受体的Fc？R相互作用则抑制炎症过程。然而，Fc？R在动脉粥样硬化的发生和发展中的作用尚不清楚。我们在易患动脉粥样硬化的apoE-/-小鼠中获得了缺乏激活或抑制Fc？R的双基因敲除小鼠，为研究Fc？R在动脉粥样硬化中的作用提供了工具。我们还观察到，除了与IC、小鼠CD16相互作用外，Fc？R还可以直接与oxLDL结合，并可能具有清道夫受体样的活性。因此，在这项建议中，我们将：(I)确定激活Fc？R在体内动脉粥样硬化中的作用；(Ii)描述激活Fc？R缺陷小鼠减轻病变的分子机制；(Iii)确定抑制性Fc？R在体内动脉粥样硬化中的作用；(Iv)表征小鼠CD16的SR样活性并确定其功能意义。这项拟议研究的完成将极大地促进我们对Fc？Rs在动脉粥样硬化进展中的作用的理解。此外，我们的发现将允许未来的治疗方法的发展，以阻断Fc？R介导的炎症，目的是阻止或防止动脉粥样硬化的进展。公共卫生相关性：动脉粥样硬化仍然是美国和其他西方国家的主要死亡原因。这项拟议研究的完成将极大地促进我们对FC？RS在动脉粥样硬化病变发展中的作用的理解。此外，它还可以通过靶向激活和/或抑制Fc？Rs来抑制动脉粥样硬化的形成，从而设计治疗方法。

DESCRIPTION (provided by applicant): Atherosclerosis is a chronic inflammatory process of the vascular endothelium that leads to cardiovascular disease. Generation of oxidized form of LDL (oxLDL) and its uptake by macrophages is an early event in the atherosclerosis. OxLDL also induces an autoimmune response as evidenced by the presence of antibody (IgG) against oxLDL and oxLDL-immune complex (oxLDL-IC) in atherosclerotic lesions in patients and animal model. The titer of autoantibodies against oxLDL is correlated with the progression of atherosclerosis in humans and in the hyperlipidemic mouse model. Therefore, oxLDL-IC could be involved in the inflammatory processes leading to the initiation and progression of atherosclerosis. We have shown that human monocytes adhere to oxLDL-IC coated endothelial cells in vitro and release inflammatory cytokines. This interaction is mediated through a group of cellular receptors called Fc gamma receptors (Fc?R), which bind immune complexes and play a major role in IC-mediated tissue injury in chronic inflammatory disease involving autoantibodies. Interaction of oxLDL-IC with Fc?Rs containing activation motif could initiate an inflammatory response while interaction with Fc?R containing the inhibitory receptor will dampen the inflammatory process. However, the role of Fc?R in initiation and progression of atherosclerosis is not known. We have generated double knock out mice lacking the activating or inhibitory Fc?R, in atherosclerosis prone apoE-/- mice, providing us tools to study the role of Fc?R during atherosclerosis. We have also observed that in addition to its interaction with IC, mouse CD16, a Fc?R can bind oxLDL directly and could have scavenger receptor like activity. Therefore in this proposal we will, (i) determine the role of activating Fc?R during atherosclerosis in vivo, (ii) delineate molecular mechanisms contributing to the attenuated lesions in the activating Fc?R deficient mice, (iii) determine the role of inhibitory Fc?R during atherosclerosis in vivo, and (iv) characterize the SR-like activity of mouse CD16 and determine its functional implications. Completion of this proposed study will significantly advance our understanding the role of Fc?Rs in the progression of atherosclerosis. Further, Our findings would allow for future development of therapeutics to block Fc?R-mediated inflammation with the goal of blocking or preventing the progression of atherosclerosis. PUBLIC HEALTH RELEVANCE: Atherosclerosis remains the leading cause of death in the USA and other Western countries. Completion of this proposed study will significantly advance our understanding the role of Fc?Rs in the lesion development during atherosclerosis. Further, it could allow for designing therapeutics by inhibiting atherogenesis via targeting activating and/or inhibitory Fc?Rs.