Complement and Macrophage Polarization in Atherosclerosis

动脉粥样硬化中的补体和巨噬细胞极化

基本信息

批准号：
8741850
负责人：
Deborah Ann Fraser
金额：
$ 10.91万
依托单位：
CALIFORNIA STATE UNIVERSITY LONG BEACH
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-05 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8741850
关键词：
Anti-Inflammatory Agents Anti-inflammatory Apoptosis Apoptotic Arterial Intimas Atherosclerosis Autoimmune Diseases Binding Cardiovascular Diseases Cause of Death Cell Line Cells Cholesterol Chronic Complement Complement 1q Complement Activation Complement Membrane Attack Complex Cytokine Gene Deposition Disease Excision Foam Cells Gene Expression Goals Homeostasis Human Hyperlipidemia Immune Immune response Immune system In Vitro Inflammation Inflammatory Inflammatory Response Ingestion Investigation Link Lipids Lipoproteins Molecular Molecular Mechanisms of Action Mus Normal tissue morphology Outcome Pathology Pathway interactions Pattern recognition receptor Perception Phagocytes Phagocytosis Phenotype Play Proteins Public Health Reporting Role Signal Transduction Staging Testing Woman complement pathway cytokine design improved in vitro testing in vivo lipid metabolism macrophage men monocyte mouse model new therapeutic target novel novel therapeutics pathogen programs public health relevance response therapeutic target

项目摘要

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.

描述（由申请人提供）：该项目的总体目标是定义补体蛋白C1Q在动脉粥样硬化中巨噬细胞极化中的作用。先天免疫蛋白C1q通常仅因其在炎症补体级联反应中的作用而被视为。但是，在没有其他补体组件的情况下，C1Q也可以直接调整目标。它是一种模式识别受体（PRR），能够直接与吞噬细胞互动并激活反应。我们先前已经显示C1Q激活巨噬细胞吞噬作用，并在凋亡细胞清除期间调节细胞因子和基因表达对M2样反应。在动脉粥样硬化的早期，改良的脂蛋白积聚在动脉内膜中，导致巨噬细胞泡沫细胞的形成和凋亡。在疾病的后期，通过C1Q的补体激活导致终端补体和胞溶膜攻击复合物的沉积，这加剧了病理。但是，相反，C1Q在动脉粥样硬化的早期阶段已被证明具有保护性，但尚未阐明其确切的作用机理。我们的中心假设是，在摄入改良的脂蛋白期间，C1Q的补体无关作用是对保护性的抗动脉粥样硬化表型的极化。我们先前已经表明，C1Q通过结合和增强动脉粥样硬化脂蛋白的清除来改变脂质代谢的途径，并增加胆固醇载荷的人类巨噬细胞中的胆固醇外排。因此，我们建议对所涉及的途径进行详细的机械研究，并确定脂质代谢途径和炎症反应之间的任何串扰。研究将在体外，原发性分离的鼠或单核细胞衍生的人巨噬细胞以及巨噬细胞系，在体内，在体内，在小鼠高脂血症模型中。这些研究旨在确定设计新型治疗策略的新途径。这些可能包括恢复或增强有缺陷的凋亡泡沫细胞清除率，增强或模仿抗炎巨噬细胞极化和/或抑制有害的末端补体途径激活。