ATHEROSCLEROTIC LESION INITIATION BY RESIDENT AORTIC MACROPHAGE PROLIFERATION AND LIPID UPTAKE

驻留主动脉巨噬细胞增殖和脂质摄取引发动脉粥样硬化病变

• 批准号: 9526863
• 负责人: Jesse Warren Williams
• 金额: $ 12.45万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-03-09 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9526863
• 关键词: Address; Affect; Animals; Aorta; Area; Arterial Fatty Streak; Arteries; Atherosclerosis; Attenuated; Birth; Blood; Blood flow; Cardiovascular Diseases; Cell Death; Cell Lineage; Cells; Cellularity; Cholesterol; Chronic; Clonality; Data; Defect; Deposition; Development; Digestion; Disease; Disease Progression; Endothelium; Event; Exposure to; Fellowship; Foam Cells; Gene Expression Profiling; Genetic Models; Grant; Hypertension; Image; Imaging Techniques; Individual; Inflammation; Inflammatory; Inflammatory Response; Label; Laboratories; Lesion; Lipids; Location; Maintenance; Mediator of activation protein; Methods; Modeling; Mononuclear; Morbidity - disease rate; Mus; Necrosis; Outcome; Pathology; Pattern; Phagocytes; Phase; Play; Population; Production; Proliferating; Proliferation Marker; Protocols documentation; Reporter; Reporting; Research; Resolution; Resources; Role; Serum; Severity of illness; Stroke; System; Testing; Therapeutic; Thrombosis; Tissues; Tracer; Tunica Adventitia; United States; Universities; Vascular Endothelium; Washington; aortic arch; base; cell motility; cytokine; diphtheria toxin receptor; early onset; experimental study; genetic profiling; genetic signature; hypercholesterolemia; imaging approach; in vivo; insight; macrophage; monocyte; mortality; mouse model; new technology; programs; recruit; trafficking; uptake

Project Summary/Abstract Cardiovascular disease is a leading cause of morbidity and mortality in the United States. Atherosclerosis is an inflammatory disease of the large and mid-sized arteries that promotes the development of cardiovascular disease through plaque formation, restricted blood flow, and ultimately thrombotic events. Chronic exposure of the arterial endothelium to elevated (and potentially modified) serum cholesterol leads to the hallmarks of pathology; including altered blood flow patterns, endothelial activation, and recruitment of blood monocytes. Infiltrating monocytes differentiate into lipid-laden plaque macrophages and contribute to the necrotic core that is a hallmark of advanced lesions. Research has focused on the role of monocytes in the maintenance of atherosclerotic plaques however; relatively few resources have been dedicated to investigating the role of tissue-resident mononuclear phagocytes (MNPs), which reside in the aortic arch. Resident MNPs reside in the nascent aorta at birth in locations where plaques have propensity to develop, and the cells are even present there in animals not susceptible to disease. My preliminary studies definitively show these cells are macrophage lineage cells, not dendritic cells as previously reported and may facilitate the onset of early plaque by importing the first quantitative load of cholesterol into the intima. Thus, these cells may be pivotal in regulating atherosclerotic plaque burden. However, technical approaches to determine if intimal resident macrophages persist in plaques and carry out distinct roles have not emerged to address this possibility. I have established protocols to track and modulate the resident intimal macrophage population independent of infiltrating blood-derived precursors like monocytes. I find that resident macrophages are the first cells to take up lipid in the aortic wall and persist through plaque development. Resident macrophages reside inside regions known to develop into necrotic core, and also form a “boarder” around the plaque itself. Further, I have developed approaches to track proliferation of macrophages within the plaque, as well as use new technologies to isolate intimal macrophages without contamination from monocytes or adventitial macrophages. Primarily using a combination of fixed- and live-imaging approaches in murine atherosclerotic plaque and taking advantage of new mouse models, I will test the hypothesis that resident aortic intimal macrophages, independent of recruited monocyte-derived macrophages, play a unique and important role in atherosclerotic plaque development. To test my hypothesis, I will assess the role of proliferation and motility in the plaques, address the differential roles of resident versus recruited monocytes in disease progression, and further develop intravital approaches to understand how interactions between monocytes and intimal macrophages may contribute to disease severity. If true, the implications of this study would greatly clarify and alter how the field might target macrophages or circulating monocytes to manage atherosclerotic disease.

项目概要/摘要 心血管疾病是美国发病率和死亡率的主要原因。 动脉粥样硬化是一种促进大中动脉发育的炎症性疾病 通过斑块形成、血流受限以及最终的血栓事件来预防心血管疾病。 动脉内皮长期暴露于升高的（且可能改变的）血清胆固醇会导致 病理学特征；包括改变血流模式、内皮激活和招募 血液单核细胞。浸润性单核细胞分化为载脂斑块巨噬细胞，并有助于 坏死核心是晚期病变的标志。研究重点是单核细胞在 然而动脉粥样硬化斑块的维持；用于调查的资源相对较少 驻留在主动脉弓的组织驻留单核吞噬细胞（MNP）的作用。常驻 MNP 出生时存在于新生主动脉中，斑块易于形成的位置，并且细胞 甚至存在于不易患病的动物体内。我的初步研究明确表明这些细胞 是巨噬细胞谱系细胞，而不是之前报道的树突状细胞，可能促进早期 通过将第一定量的胆固醇导入内膜来去除斑块。因此，这些细胞可能在 调节动脉粥样硬化斑块负荷。然而，确定内膜是否存在的技术方法 巨噬细胞持续存在于斑块中并发挥独特的作用，但尚未解决这种可能性。 我已经建立了跟踪和调节常驻内膜巨噬细胞群的方案 独立于单核细胞等浸润性血液前体细胞。我发现常驻巨噬细胞是 第一个细胞吸收主动脉壁中的脂质并在斑块形成过程中持续存在。常驻巨噬细胞 存在于已知会发展成坏死核心的区域内，并且还在斑块本身周围形成“边界”。 此外，我还开发了追踪斑块内巨噬细胞增殖的方法，以及使用 分离内膜巨噬细胞而不受单核细胞或外膜污染的新技术 巨噬细胞。主要结合使用固定成像和实时成像方法来治疗小鼠动脉粥样硬化 斑块并利用新的小鼠模型，我将检验以下假设：驻留主动脉内膜 巨噬细胞独立于招募的单核细胞衍生的巨噬细胞，发挥着独特而重要的作用 动脉粥样硬化斑块发展中的作用。为了检验我的假设，我将评估增殖和 斑块的运动性，解决常驻单核细胞与招募单核细胞在疾病中的不同作用 进展，并进一步开发活体方法来了解单核细胞和单核细胞之间的相互作用 内膜巨噬细胞可能导致疾病严重程度。如果属实，这项研究的意义将极大 阐明并改变该领域如何针对巨噬细胞或循环单核细胞来控制动脉粥样硬化 疾病。

项目成果

Brown adipose tissue monocytes support tissue expansion.

• DOI: 10.1038/s41467-021-25616-1
• 发表时间: 2021-09-06
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Gallerand A;Stunault MI;Merlin J;Luehmann HP;Sultan DH;Firulyova MM;Magnone V;Khedher N;Jalil A;Dolfi B;Castiglione A;Dumont A;Ayrault M;Vaillant N;Gilleron J;Barbry P;Dombrowicz D;Mack M;Masson D;Bertero T;Becher B;Williams JW;Zaitsev K;Liu Y;Guinamard RR;Yvan-Charvet L;Ivanov S
• 通讯作者: Ivanov S