Ⅰ型干扰素激活PFKFB3驱动的糖酵解促进巨噬细胞的抗病毒先天免疫

发布时间：2018-08-02 15:55

【摘要】：先天免疫系统为机体抵抗病毒感染提供重要的保护。通过对病毒核酸的模式识别,机体激活先天免疫反应产生大量的一型干扰素。后者在抗病毒免疫中具有举足轻重的作用。然而到目前为止仍然不清楚的是一型干扰素是否通过调控机体的细胞代谢从而作为机体抵抗病毒的一种机制。葡萄糖代谢作为细胞能量代谢的中心,近些年来越来越多的被认为参与调控细胞生命活动的各个方面。葡萄糖的无氧分解代谢也被称为糖酵解是葡萄糖代谢过程中最初的步骤,不但为细胞的生命活动快速地提供能量ATP,而且生成中间产物参与各种生物大分子的合成,为细胞增殖提供物质基础。越来越多的证据表明糖酵解在不同的细胞的生命活动过程中是被精确调控的。因此,我们的研究重点主要关注在不同类型的细胞中葡萄糖代谢与抗病毒先天免疫的关联以及相互作用。我们的研究发现抗病毒先天免疫新的代谢关联,病毒感染产生的一型干扰素(IFN)选择性的在巨噬细胞而不是小鼠胚胎成纤维细胞中上调糖酵解。研究发现这一现象是由于一型干扰素在巨噬细胞中特异性的上调6-磷酸果糖-2激酶／果糖-2,6-二磷酸酶(PFKFB3)基因的表达。功能获得性以及功能缺失性实验表明,PFKFB3是糖酵解流量的控制的关键酶。有趣的是来源于PFKFB3突变的杂合子小鼠的巨噬细胞而不是胚胎成纤维细胞表现出对病毒感染的易感性。后者的实验结果表明尽管糖酵解有助于生物合成的过程和病毒在宿主细胞内的增殖,PFKFB3蛋白水平适中地下降并不影响病毒相关的合成。进一步研究证实PFKFB3驱动的糖酵解是通过提升巨噬细胞的吞噬能力来促进其抗病毒功能。的确我们的实验结果表明IFN诱导的糖酵解会增强巨噬细胞的吞噬效率使受病毒感染的细胞更有效的被吞噬清除掉。在吞噬过程中,PFKFB3会即时地被招募到吞噬小泡周围新形成的肌动蛋白微丝上,可能为快速的肌动蛋白聚合提供能量ATP。此外,因为磷脂酰肌醇3-激酶(PI3K)信号通路的活性调控对吞噬作用的完成是必须的条件,我们发现PFKFB3表达水平与PI3K的信号通路的活性呈正相关性。因此PFKFB3调控PI3K信号通路可能也是PFKFB3促进巨噬细胞的吞噬的机制。综上所述,我们的实验结果表明巨噬细胞特异性的代谢调控有助于抗病毒先天免疫。这一研究有助于我们更好的理解细胞代谢与先天免疫的相互关联与作用。这两者间的相互调控机制为抗病毒天然免疫药物的开发提供潜在的靶点。
[Abstract]:Innate immune system provides important protection against virus infection. By pattern recognition of viral nucleic acids, the body activates the innate immune response to produce a large number of interferon-1 types. The latter plays an important role in anti-viral immunity. However, it is still unclear whether interferon I may act as a mechanism for virus resistance by regulating cell metabolism. As the center of cell energy metabolism, glucose metabolism is considered to be involved in various aspects of cell life in recent years. Anaerobic catabolism of glucose, also known as glycolysis, is the first step in glucose metabolism. It not only provides energy for cell life activities rapidly, but also produces intermediates to participate in the synthesis of various biomolecules. To provide material basis for cell proliferation. There is growing evidence that glycolysis is precisely regulated in the life of different cells. Therefore, our research focuses on the relationship and interaction between glucose metabolism and antiviral innate immunity in different types of cells. Our study found a new metabolic association of innate immunity against viruses. Type I interferon (IFN) produced by viral infection selectively upregulated glycolysis in macrophages rather than mouse embryonic fibroblasts. This phenomenon is due to the specific up-regulation of fructose-2-kinase / fructose-2-diphosphatase (PFKFB3) gene expression in macrophages. The results of functional acquisition and functional deletion showed that PFKFB3 was the key enzyme in the control of glycolysis flow. Interestingly, macrophages from heterozygous mice derived from PFKFB3 mutations, rather than embryonic fibroblasts, showed susceptibility to viral infection. The results of the latter study showed that although glycolysis contributed to the biosynthesis process and the moderate decrease in the protein level of PFKFB3 in host cells did not affect the virus-related synthesis. Further studies have demonstrated that PFKFB3-driven glycolysis promotes the antiviral function of macrophages by enhancing their phagocytosis. Indeed, our results suggest that IFN-induced glycolysis enhances the phagocytosis of macrophages so that virus-infected cells are more effectively phagocytized and eliminated. During phagocytosis, PFKFB3 is immediately recruited to the newly formed actin microfilaments around the phagocytic vesicles, which may provide energy for rapid actin polymerization. In addition, since the activity regulation of phosphatidylinositol 3-kinase (PI3K) signaling pathway is necessary for the completion of phagocytosis, we found that the level of PFKFB3 expression was positively correlated with the activity of PI3K signaling pathway. Therefore, the regulation of PI3K signaling pathway by PFKFB3 may also be the mechanism of PFKFB3 promoting phagocytosis of macrophages. In conclusion, our results suggest that macrophage specific metabolic regulation contributes to anti-viral innate immunity. This study helps us to better understand the relationship between cellular metabolism and innate immunity. The mutual regulation mechanism between the two provides a potential target for the development of antiviral innate immunopharmaceuticals.
【学位授予单位】：南京大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R392

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