Substrate Fate in Activated Macrophages: A Comparison between Innate, Classic, and Alternative Activation
Substrate Fate in Activated Macrophages: A Comparison between Innate, Classic, and Alternative Activation
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DOI：
10.4049/jimmunol.0901698
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发表时间：
2010-07-01
影响因子：
4.4
通讯作者：
Bosca, Lisardo
中科院分区：
文献类型：
--
作者：
Rodriguez-Prados, Juan-Carlos;Traves, Paqui G.;Bosca, Lisardo
巨噬细胞在先天免疫和获得性免疫中发挥着相关的作用，这取决于所接受的刺激的平衡。从分析和功能的角度来看，巨噬细胞刺激可分为三种主要方式：先天途径、经典途径和替代途径。这些不同的激活导致特定的基因集合的表达，这些基因参与了促炎或抗炎刺激的释放。在目前的工作中，我们分析了特定的代谢模式是否依赖于激活的信号通路。一种基于[1，2-C-13(2)]葡萄糖示踪剂的代谢组学方法已经被用来表征通过经典的、天然的和替代的途径刺激的巨噬细胞的代谢通量分布。利用这种方法结合对新形成的代谢产物的质量同位异体分布的分析，数据表明，激活的巨噬细胞本质上是糖酵解细胞，经典/天然激活和替代途径之间存在明显的分界线。有趣的是，巨噬细胞通过内毒素/干扰素-γ或TLR-2、-3、-4和-9激活时，无论激活的途径是什么，都会导致相似的流量分布模式。然而，通过替代途径的刺激对新陈代谢的影响很小。这两种行为差异的分子基础涉及6-phosphofructo-2-kinase/fructose-2，6-bisphosphatase(PFK2)的表达从肝型PFK2切换到更活跃的普遍存在的PFK2同工酶，该同工酶对HIF-1α激活做出反应，并增加2，6-二磷酸果糖浓度和糖酵解通量。然而，使用针对Hif-1α的巨噬细胞，在内毒素/干扰素-γ激活的巨噬细胞中仍然发生PFK2同工酶的切换，表明这一途径通过Hif-1α不依赖的机制来调节普遍存在的PFK2的表达。免疫学杂志，2010,185：605-614。
Macrophages play a relevant role in innate and adaptive immunity depending on the balance of the stimuli received. From an analytical and functional point of view, macrophage stimulation can be segregated into three main modes, as follows: innate, classic, and alternative pathways. These differential activations result in the expression of specific sets of genes involved in the release of pro- or anti-inflammatory stimuli. In the present work, we have analyzed whether specific metabolic patterns depend on the signaling pathway activated. A [1,2-C-13(2)]glucose tracer-based metabolomics approach has been used to characterize the metabolic flux distributions in macrophages stimulated through the classic, innate, and alternative pathways. Using this methodology combined with mass isotopomer distribution analysis of the new formed metabolites, the data show that activated macrophages are essentially glycolytic cells, and a clear cutoff between the classic/innate activation and the alternative pathway exists. Interestingly, macrophage activation through LPS/IFN-gamma or TLR-2, -3, -4, and -9 results in similar flux distribution patterns regardless of the pathway activated. However, stimulation through the alternative pathway has minor metabolic effects. The molecular basis of the differences between these two types of behavior involves a switch in the expression of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK2) from the liver type-PFK2 to the more active ubiquitous PFK2 isoenzyme, which responds to Hif-1 alpha activation and increases fructose-2,6-bisphosphate concentration and the glycolytic flux. However, using macrophages targeted for Hif-1 alpha, the switch of PFK2 isoenzymes still occurs in LPS/IFN-gamma-activated macrophages, suggesting that this pathway regulates ubiquitous PFK2 expression through Hif-1 alpha-independent mechanisms. The Journal of Immunology, 2010, 185: 605-614.