Role of Fc gamma receptors in atherosclerosis

描述（申请人提供）：动脉粥样硬化是导致心血管疾病的血管内皮的慢性炎症过程。氧化形式的低密度脂蛋白（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还诱导自身免疫反应，这一点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）。在人类和高脂血症小鼠模型中，抗oxLDL自身抗体的滴度与动脉粥样硬化的进展相关。因此，oxLDL-IC可能参与导致动脉粥样硬化发生和发展的炎症过程。我们已经证明，人单核细胞粘附在体外oxLDL-IC包被的内皮细胞上并释放炎症细胞因子。这种相互作用是通过一组称为Fc γ受体(Fc？R)，结合免疫复合物并在ic介导的慢性炎症性疾病（涉及自身抗体）的组织损伤中起主要作用。oxLDL-IC与Fc？含有活化基序的Rs与Fc？含有抑制受体的R会抑制炎症过程。然而，Fc？R在动脉粥样硬化发生和发展中的作用尚不清楚。我们产生了双敲除小鼠缺乏激活或抑制Fc？R，在动脉粥样硬化易发apoE-/-小鼠中，为我们研究Fc？R在动脉粥样硬化期间。我们还观察到，除了与IC、小鼠CD16、Fc？R可直接结合oxLDL，具有类似清道夫受体的活性。因此，在本提案中，我们将(i)确定激活Fc？在体内动脉粥样硬化期间，（ii）描述激活Fc？R缺陷小鼠，（iii）确定抑制Fc？（iv）表征小鼠CD16的sr样活性并确定其功能意义。这项研究的完成将大大促进我们对Fc？Rs对动脉粥样硬化的影响此外，我们的研究结果将允许未来开发阻断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：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。这项研究的完成将大大促进我们对Fc？Rs在动脉粥样硬化过程中的病变发展。此外，它可以通过靶向激活和/或抑制Fc来设计抑制动脉粥样硬化的疗法。Rs。

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.