MACROPHAGE FATTY ACID METABOLISM IN IMMUNITY TO HELMINTHS

 描述(申请人提供)：蠕虫寄生虫是许多发展中国家的地方病。这些病原体造成的疾病总负担很高，约有3亿感染者患有严重疾病。在这里，我们将重点关注M2巨噬细胞，它们在蠕虫感染中发挥着关键的宿主保护作用。巨噬细胞可以根据情况采取不同的激活状态。干扰素与TLR激动剂联合可促进M1(或经典)激活，而细胞因子IL-4和IL-13可促进M2(或交替)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，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，粮农组织已被证明是M2激活所必需的。这一认识将我们的注意力集中在脂肪酸代谢上，由于脂肪酸对M2的激活是必不可少的，因此从定义上讲，它必须是抵御蠕虫感染的重要方面。粮农组织的脂肪酸来自三酰甘油的溶酶体脂肪分解，三酰甘油来自外部或通过脂肪酸的内源合成。尽管粮农组织显然对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FAO作为柠檬酸的有效来源输出到细胞质中，在那里它可以用于M2激活的关键过程，例如FAO合成脂肪酸并作为PPAR的配体，以及生产醋酸盐用于组蛋白的乙酰化以允许M2基因的表达。除了它们在免疫中的作用 对蠕虫来说，M2巨噬细胞在伤口愈合和全身代谢动态平衡中发挥作用。值得注意的是，据报道，蠕虫感染能够缓解高脂肪饮食的新陈代谢后果。我们假设蠕虫感染诱导的强大的2型免疫能够通过广泛支持感染部位远端组织中M2的激活来维持代谢动态平衡，并将在我们的第三个目标中进行探索。这个项目的具体目标是：1.确定M2是否需要脂肪酸合成 激活。2.研究组蛋白乙酰化在M2活化中的代谢调控作用。3.确定蠕虫感染中的2型免疫是否通过广泛支持M2激活来调节代谢动态平衡。我们将使用遗传功能丧失和化学抑制的方法来靶向编码参与脂代谢的酶、转录因子和受体的关键基因，以探索还原系统中和感染蠕虫寄生虫期间M2的激活。我们将研究感染这些微生物后脂代谢变化的结果，并将研究蠕虫感染对肥胖相关代谢紊乱有益影响的潜在基础。

 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.