MACROPHAGE FATTY ACID METABOLISM IN IMMUNITY TO HELMINTHS

蠕虫免疫中的巨噬细胞脂肪酸代谢

基本信息

批准号：
8887045
负责人：
EDWARD J. PEARCE
金额：
$ 38.13万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-01-13 至 2015-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8887045
关键词：
Acetates Acid Lipase Address Adipose tissue Adopted Agonist Attention CD36 gene Cell Respiration Cells Chemicals Chronic Citrates Citric Acid Cycle Cytosol Developing Countries Diet Disease Distal Enzymes Exhibits Face Fatty Acids Fatty acid glycerol esters Gene Expression Genes Genetic Glucose Glutamine Grant Health Helminths Hepatocyte Histone Acetylation Homeostasis Host Defense Immune response Immunity Infection Inflammation Inflammatory Injection of therapeutic agent Interferons Interleukin-13 Interleukin-4 Ligands Lipolysis Liver Macrophage Activation Mediating Mediator of activation protein Metabolic Metabolic Control Metabolic Diseases Metabolism Mitochondria Morbidity - disease rate Nematoda Nematospiroides dubius Nutrient Obesity Organ Organism Outcome Oxidative Phosphorylation Oxygen Consumption Parasites Platyhelminths Play Process Production Publications Reporting Research Resistance to infection Rest Role STAT6 Transcription Factor Schistosoma mansoni Site Societies Source System T-Cell Proliferation Time Tissues Triglycerides Wound Healing adaptive immunity aerobic glycolysis base burden of illness cell type cytokine fatty acid metabolism fatty acid oxidation inhibitor/antagonist lipid metabolism loss of function macrophage microbial neglected tropical diseases oxidation pathogen preference programs receptor respiratory response tissue repair transcription factor uptake

项目摘要

DESCRIPTION (provided by applicant): Helminth parasites are endemic in many developing countries. The overall burden of disease due to these pathogens is high, with approximately 300 million infected people suffering from severe morbidity. Here we will focus on M2 macrophages, which play crucial host protective roles in helminth infections. Macrophages can adopt different activation states depending on context. Interferon-γ in combination with TLR agonists promotes M1 (or classical) activation, whereas the cytokines IL-4 and IL-13 promote M2 (or alternative) activation. Differential functions in M1 and M2 macrophages are supported by distinct core metabolisms, with M1 cells committing to aerobic glycolysis, and M2 macrophages utilizing fatty acid oxidation (FAO) and mitochondrial oxidative phosphorylation. Indeed, FAO has been shown to be necessary for M2 activation. This realization has focused our attention on fatty acid metabolism, which since it is essential for M2 activation must, by definition, be an essential face of protection against helminth infections. Fatty acids for FAO are derived from the lysosomal lipolysis of triacylglycerols, which are sourced either from the exterior or through endogenous synthesis of fatty acids. Despite the fact that it is clear that FAO is essential for M2 activation the underlying reasons for the importance of this type of metabolism for M2 activation are unclear. We hypothesize that FAO serves as an efficient source of citrate for export into the cytosol where it can be used for processes that are critical for M2 activation such as synthesis of fatty acids for FAO and to act as ligands for PPARs, and the production of acetate for the acetylation of histones to permit the expression of M2 genes. In addition to their role in immunity to helminths, M2 macrophages play roles in wound healing, and in whole body metabolic homeostasis. Remarkably, helminth infection has been reported to be capable of mitigating the metabolic consequences of a high fat diet. We hypothesize that strong type 2 immunity induced by helminth infection is able to maintain metabolic homeostasis by broadly supporting M2 activation in tissues distal to the site of infection and will explore this in our third aim. The specific aims of this project are: 1. To establish whether fatty acid synthesis is necessary for M2 activation. 2. To assess the metabolic control of histone acetylation in M2 activation. 3. To determine whether type 2 immunity in helminth infection modulates metabolic homeostasis by broadly supporting M2 activation. We will use genetic loss of function and chemical inhibitor approaches to target key genes encoding enzymes, transcription factors and receptors involved in lipid metabolism to explore M2 activation in reductionist systems and during infection with helminth parasites. We will examine the outcome of alterations in lipid metabolism on infection with these organisms, and will examine the underlying basis for beneficial effects of helminth infections on metabolic disorders associated with obesity.

描述（由申请人提供）：蠕虫寄生虫在许多发展中国家流行，这些病原体造成的疾病总体负担很高，大约有 3 亿感染者患有严重的疾病。在这里，我们将重点关注发挥关键作用的 M2 巨噬细胞。巨噬细胞在蠕虫感染中的宿主保护作用可以根据情况采取不同的激活状态，与 TLR 激动剂结合可促进 M1（或经典）激活。细胞因子 IL-4 和 IL-13 促进 M2（或替代）激活 M1 和 M2 巨噬细胞的差异功能由不同的核心代谢支持，M1 细胞致力于有氧糖酵解，而 M2 巨噬细胞利用脂肪酸氧化 (FAO) 和线粒体。事实上，FAO 已被证明对于 M2 激活是必需的，这一认识使我们将注意力集中在脂肪酸代谢上，因为它对于 M2 激活至关重要。根据定义，脂肪酸必须是预防蠕虫感染的一个重要方面。FAO 的脂肪酸源自三酰甘油的溶酶体脂肪分解，而三酰甘油的来源要么来自外部，要么来自脂肪酸的内源合成。尽管FAO对于M2激活至关重要，但这种类型的代谢对于M2激活的重要性尚不清楚。我们努力将FAO作为柠檬酸输出到细胞质的有效来源。它可用于对 M2 激活至关重要的过程，例如合成FAO的脂肪酸并充当PPAR的配体，以及产生用于组蛋白乙酰化的乙酸盐以允许M2基因的表达。在免疫中的作用对于蠕虫来说，M2 巨噬细胞在伤口愈合和全身代谢稳态中发挥着重要作用。值得注意的是，据报道，蠕虫感染能够减轻高脂肪饮食引起的代谢后果。能够通过广泛支持感染部位远端组织中的 M2 激活来维持代谢稳态，并将在我们的第三个目标中对此进行探索。 1. 建立。 2. 评估 M2 激活中组蛋白乙酰化的代谢控制。 3. 确定蠕虫感染中的 2 型免疫是否通过广泛支持 M2 激活来调节代谢稳态。我们将使用功能和化学抑制剂方法来靶向编码参与脂质代谢的酶、转录因子和受体的关键基因，以探索还原系统中和蠕虫寄生虫感染期间的 M2 激活。脂质代谢对这些生物体感染的影响，并将研究蠕虫感染对肥胖相关代谢紊乱有益影响的根本基础。