Complement and Macrophage Polarization in Atherosclerosis

描述(由申请人提供)：本项目的总体目标是确定补体蛋白C1q在动脉粥样硬化中巨噬细胞极化编程中的作用。先天免疫蛋白C1q通常只被认为是在炎性补体级联反应中的激活作用。然而，在没有其他补体成分的情况下，C1q也可以直接调理靶点。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。我们之前已经证明，在凋亡细胞清除过程中，C1q激活巨噬细胞吞噬功能，并调节细胞因子和基因表达，从而产生类似M2的反应。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聚，导致巨噬细胞泡沫细胞的形成和凋亡。在疾病的晚期，补体通过C1q激活，导致补体的最终途径和细胞膜攻击复合体的沉积，从而加剧了病理。然而，相反，C1q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，C1q的补体非依赖性作用使巨噬细胞在摄入修饰的脂蛋白过程中极化为保护性的、抗动脉粥样硬化的表型。我们之前已经证明，C1q通过结合和促进致动脉粥样硬化的脂蛋白的清除来改变脂质代谢的途径，并增加胆固醇负载的人巨噬细胞中的胆固醇外流。因此，我们建议对所涉及的途径进行详细的机制研究，并确定脂代谢途径和炎症反应之间的任何串扰。研究将在体外、原代分离的小鼠或单核细胞来源的人类巨噬细胞、巨噬细胞系以及体内高脂血症的小鼠模型中进行。这些研究旨在为设计新的治疗策略确定新的途径。这些策略可能包括恢复或增强缺陷的凋亡泡沫细胞清除，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激活。

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.