Complement and Macrophage Polarization in Atherosclerosis

描述（由申请人提供）： 该项目的总体目标是确定补体蛋白C1 q在动脉粥样硬化中编程巨噬细胞极化中的作用。天然免疫蛋白C1 q通常仅被认为在炎症补体级联激活中起作用。然而，在缺乏其他补体成分的情况下，C1 q也可以直接调理靶标。它是一种模式识别受体（PRR），能够直接与吞噬细胞相互作用并激活反应。我们以前已经表明，C1 q激活巨噬细胞吞噬作用，并调节细胞因子和基因表达对M2样反应在凋亡细胞清除。在动脉粥样硬化的早期阶段，修饰的脂蛋白在动脉内膜中积累，导致巨噬细胞泡沫细胞的形成和凋亡。在疾病的晚期，通过C1 q的补体激活导致补体的终末途径和溶细胞膜攻击复合物的沉积，这加剧了病理。然而，相反，C1 q已被证明在动脉粥样硬化的早期阶段具有保护作用，但其确切的作用机制尚未阐明。我们的中心假设是，补体独立的行动C1 q极化巨噬细胞对一个保护性的，抗动脉粥样硬化的表型，在摄入修饰脂蛋白。我们以前已经表明，C1 q通过结合和增强致动脉粥样硬化脂蛋白的清除来改变脂质代谢途径，并增加胆固醇负载的人巨噬细胞中的胆固醇流出。因此，我们建议进行详细的机制调查的途径，并确定脂质代谢和炎症反应的途径之间的任何串扰。研究将在体外、原代分离的鼠或单核细胞衍生的人巨噬细胞和巨噬细胞系中进行，并在体内、高脂血症小鼠模型中进行。这些研究旨在确定新的途径，以设计新的治疗策略。这些可以包括恢复或增加缺陷性凋亡泡沫细胞清除、增强或模拟抗炎巨噬细胞极化和/或抑制有害的末端补体途径活化的策略。

DESCRIPTION (provided by applicant): The overall goal of this project is to define the role of complement protein C1q in programming macrophage polarization in atherosclerosis. Innate immune protein C1q is often considered only for its role in the activation of the inflammatory complement cascade. However, in the absence of other complement components, C1q can also directly opsonize targets. It is a pattern recognition receptor (PRR) and is able to directly interct with phagocytic cells and activate responses. We have previously shown C1q activates macrophage phagocytosis and modulates cytokine and gene expression towards an M2-like response during apoptotic cell clearance. In the early stages of atherosclerosis, modified lipoproteins accumulate in the arterial intima leading to the formation and apoptosis of macrophage foam cells. In late stages of disease, complement activation via C1q leads to the terminal pathway of complement and deposition of the cytolytic membrane attack complex, which exacerbates pathology. However, conversely, C1q has been shown to be protective in early stages of atherosclerosis, but its precise mechanism of action has not yet been elucidated. Our central hypothesis is that complement-independent actions of C1q are polarizing macrophages towards a protective, anti-atherosclerotic phenotype during ingestion of modified lipoproteins. We have previously shown that C1q alters pathways of lipid metabolism by binding and enhancing clearance of atherogenic lipoproteins, and increases cholesterol efflux in cholesterol-loaded human macrophages. Thus, we propose to perform detailed mechanistic investigations of the pathways involved, and to identify any cross-talk between pathways of lipid metabolism and inflammatory responses. Studies will be performed in vitro, in primary isolated murine or monocyte-derived human macrophages, and macrophage cell lines and, in vivo, in mouse models of hyperlipidemia. These studies aim to identify novel pathways for the design of novel therapeutic strategies. These may include strategies to restore or augment defective apoptotic foam cell clearance, enhance or mimic anti-inflammatory macrophage polarization, and/or inhibit detrimental terminal complement pathway activation.