MACROPHAGE FATTY ACID METABOLISM IN IMMUNITY TO HELMINTHS

描述（由申请人提供）：寄生虫是许多发展中国家的地方病。这些病原体造成的总体疾病负担很高，约有3亿受感染者患有严重发病率。在这里，我们将重点关注M2巨噬细胞，它在蠕虫感染中起着至关重要的宿主保护作用。巨噬细胞可以根据不同的环境采取不同的激活状态。干扰素-γ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巨噬细胞的不同功能是由不同的核心代谢支持的，M1细胞进行有氧糖酵解，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激活的必要条件。这一认识将我们的注意力集中在脂肪酸代谢上，由于它是M2激活所必需的，因此根据定义，它必须是防止蠕虫感染的重要方面。粮农组织的脂肪酸来自于溶酶体对三酰甘油的脂解，其来源或来自外部，或来自内源性脂肪酸合成。尽管很明显，粮农组织对M2的激活至关重要，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是柠檬酸盐的有效来源，可以出口到细胞质中，在细胞质中，它可以用于对M2激活至关重要的过程，如为FAO合成脂肪酸和作为ppar的配体，以及为组蛋白乙酰化生产醋酸盐，以允许M2基因的表达。除了它们在免疫中的作用

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.