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：
9187865
负责人：
EDWARD J. PEARCE
金额：
$ 27万
依托单位：
INSTITUT FUR IMMUNBIOLOGIE/EPIGENETIK
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 2019-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9187865
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 Gene Expression Genes Genetic Genetic Transcription Glucose Glutamine Grant Helminths Hepatocyte High Fat Diet Histone Acetylation Homeostasis Host Defense Immune response Immunity Infection Inflammation Inflammatory Injection of therapeutic agent Interferon Type II 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 STAT4 protein Schistosoma mansoni Site Societies Source System T-Cell Proliferation Time Tissues Triglycerides Wound Healing adaptive immunity aerobic glycolysis 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 public health relevance 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-¿ 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（由适用提供）：在许多发展中国家，蠕虫寄生虫是内在的。这些病原体引起的疾病的总体燃烧很高，大约3亿感染了严重发病率。在这里，我们将重点关注M2巨噬细胞，这些巨噬细胞在保护蠕虫感染中的角色至关重要。巨噬细胞可以根据上下文采用不同的激活状态。干扰素与TLR激动剂联合促进M1（或经典）激活，而细胞因子IL-4和IL-13促进M2（或替代）激活。 M1和M2巨噬细胞中的差异功能由不同的核心代谢，M1细胞承诺有氧糖酵解，以及利用脂肪酸氧化（FAO）和线粒体氧化磷酸化的M2巨噬细胞。实际上，粮农组织已被证明是M2激活所必需的。这种认识将我们的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，必须是保护蠕虫感染的必不可少的面孔。粮农组织的脂肪酸源自三酰基甘油的溶酶体脂解，这些脂肪液来自外部或内源性脂肪酸的合成。尽管很明显，FAO对于M2激活至关重要，但这种代谢对M2激活的重要性的根本原因尚不清楚。我们假设粮农组织是柠檬酸粮农组织的有效来源，用于导出到细胞质中，在其中它可用于对M2激活至关重要的过程，例如fao的合成脂肪酸的合成，并用作PPARS的配体，并用作乙酸盐的产生，以允许M2基因的乙酸乙酸酯的产生。除了它们在免疫中的作用对于舵手，M2巨噬细胞在伤口愈合和全身代谢稳态中扮演角色。值得注意的是，据报道，蠕虫感染能够减轻高脂饮食的代谢后果。我们假设由蠕虫感染引起的强大的2型免疫诱导能够通过广泛支持感染部位的组织中的M2激活来维持代谢稳态，并将在我们的第三个目标中探索这一点。该项目的具体目的是：1。确定M2是否需要脂肪酸合成激活。 2。评估M2激活中组蛋白乙酰化的代谢控制。 3。确定2型免疫支持是否通过广泛支持M2激活来代谢稳态。我们将使用功能和化学抑制剂方法的遗传丧失来靶向编码脂质代谢中涉及的酶，转录因子和受体的关键基因，以探索还原主义系统中的M2激活以及在使用蠕虫寄生虫感染期间。我们将研究这些生物感染脂质代谢改变的变化的结果，并将检查蠕虫感染对与肥胖相关的代谢疾病的有益影响的基础。