Role of Fc gamma receptors in atherosclerosis

描述（由申请方提供）：动脉粥样硬化是一种导致心血管疾病的血管内皮慢性炎症过程。氧化型低密度脂蛋白（oxLDL）的产生及其被巨噬细胞摄取是动脉粥样硬化的早期事件。oxLDL还诱导自身免疫应答，如在患者和动物模型中动脉粥样硬化病变中存在针对oxLDL和oxLDL-免疫复合物（oxLDL-IC）的抗体（IgG）所证明的。抗oxLDL自身抗体的滴度与人类和高脂血症小鼠模型中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。我们已经表明，人单核细胞粘附oxLDL-IC包被的内皮细胞在体外释放炎性细胞因子。这种相互作用是通过一组称为Fc γ受体（Fc？R），其结合免疫复合物并在涉及自身抗体的慢性炎性疾病中的IC介导的组织损伤中起主要作用。oxLDL-IC与Fc？含有激活基序的Rs与Fc？含有抑制性受体的R将抑制炎症过程。然而，Fc的作用？R在动脉粥样硬化发生和发展中的作用尚不清楚。我们已经产生了双敲除小鼠缺乏激活或抑制Fc？R，在动脉粥样硬化倾向apoE-/-小鼠，为我们提供了工具，研究Fc？动脉粥样硬化期间。我们还观察到，除了其与IC的相互作用，小鼠CD 16，Fc？R可直接与oxLDL结合，具有清道夫受体样活性。因此，在本提案中，我们将，（i）确定激活Fc的作用？R动脉粥样硬化在体内，（ii）描绘分子机制，有助于衰减病变的激活Fc？R缺陷小鼠，（iii）确定抑制性Fc？R动脉粥样硬化在体内，和（iv）表征SR样活性的小鼠CD 16，并确定其功能的影响。完成这项拟议的研究将显着推进我们的理解Fc的作用？在动脉粥样硬化的进展中。此外，我们的研究结果将允许未来开发的治疗方法，以阻止Fc？R介导的炎症，目的是阻断或预防动脉粥样硬化的进展。公共卫生相关性：在美国和其他西方国家，动脉粥样硬化仍然是导致死亡的主要原因。完成这项拟议的研究将显着推进我们的理解Fc的作用？Rs在动脉粥样硬化病变发展中的作用。此外，它可以允许通过靶向激活和/或抑制Fc？卢比

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.