MACROPHAGE FATTY ACID METABOLISM IN IMMUNITY TO HELMINTHS

蠕虫免疫中的巨噬细胞脂肪酸代谢

• 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
• 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

 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 亿感染者病情严重。在这里，我们将重点关注 M2 巨噬细胞，它在蠕虫感染中发挥着至关重要的宿主保护作用。巨噬细胞可以根据环境采取不同的激活状态。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 则促进 M2（或替代）激活。 M1 和 M2 巨噬细胞的不同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) 和线粒体氧化磷酸化。事实上，FAO 已被证明对于 M2 的激活是必要的。这一认识将我们的注意力集中在脂肪酸代谢上，因为脂肪酸代谢对于 M2 激活至关重要，根据定义，它必然是预防蠕虫感染的一个重要方面。用于FAO的脂肪酸源自三酰甘油的溶酶体脂肪分解，其来源于外部或通过脂肪酸的内源合成。尽管事实上，FAO 对于 M2 激活至关重要，但这种类型的代谢对于 M2 激活的重要性的根本原因尚不清楚。我们假设FAO是柠檬酸盐的有效来源，可输出到细胞质中，可用于对M2激活至关重要的过程，例如FAO的脂肪酸合成和作为PPAR的配体，以及组蛋白乙酰化产生乙酸以允许M2基因的表达。除了它们在免疫方面的作用 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作用。值得注意的是，据报道，蠕虫感染能够减轻高脂肪饮食的代谢后果。我们假设由蠕虫感染诱导的强 2 型免疫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。该项目的具体目标是： 1. 确定脂肪酸合成是否是 M2 所必需的 激活。 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。我们将利用遗传功能丧失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。我们将研究这些生物体感染后脂质代谢变化的结果，并将研究蠕虫感染对与肥胖相关的代谢紊乱产生有益影响的根本基础。