HIF-1α and PFKFB3 Mediate a Tight Relationship Between Proinflammatory Activation and Anerobic Metabolism in Atherosclerotic Macrophages.
HIF-1α and PFKFB3 Mediate a Tight Relationship Between Proinflammatory Activation and Anerobic Metabolism in Atherosclerotic Macrophages.
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DOI：
10.1161/atvbaha.115.305551
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发表时间：
2015-06
期刊：
影响因子：
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通讯作者：
Boscá L
中科院分区：
文献类型：
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作者：
Tawakol A;Singh P;Mojena M;Pimentel-Santillana M;Emami H;MacNabb M;Rudd JH;Narula J;Enriquez JA;Través PG;Fernández-Velasco M;Bartrons R;Martín-Sanz P;Fayad ZA;Tejedor A;Boscá L
虽然人们普遍认为，在缺氧条件下，巨噬细胞糖酵解会上调，但尚不清楚这是否与巨噬细胞促炎激活的类似增加有关，也不清楚特定的能量需求是否会调节动脉粥样硬化斑块中的细胞活力。我们研究了动脉粥样硬化背景下巨噬细胞能量代谢、极化和活力之间的相互作用。通过培养的人和小鼠巨噬细胞以及小鼠体内动脉粥样硬化模型来评估巨噬细胞在不同动脉粥样硬化条件下代谢和炎症活性的机制。我们观察到巨噬细胞的能量与炎症激活密切线性相关，因此需要动态校准糖酵解以跟上炎症活动的步伐。此外，我们发现巨噬细胞糖酵解和促炎激活主要依赖于缺氧诱导因子（HIF）及其对葡萄糖摄取的影响，以及己糖激酶II和普遍存在的6-磷酸果糖-2激酶（PFKFB3）的表达。因此，缺氧主要通过这些途径增强炎症和糖酵解。此外，当巨噬细胞通过PFKFB3增加糖酵解的能力在实验中减弱时，细胞活力在促炎和/或缺氧条件下降低，但在对照条件下不受影响。除此之外，GM-CSF增强无氧糖酵解，同时发挥轻微的促炎激活作用。这些在人类和小鼠细胞以及动物模型中的发现表明，缺氧增强巨噬细胞糖酵解通量，并以一种依赖于HIF-1α和PFKFB3的方式，成比例地上调促炎活性。
While it is accepted that macrophage glycolysis is up-regulated under hypoxic conditions, it is not known whether this is linked to a similar increase in macrophage pro-inflammatory activation and whether specific energy demands regulate cell viability in the atheromatous plaque. We studied the interplay between macrophage energy metabolism, polarization and viability in the context of atherosclerosis. Cultured human and murine macrophages and an in vivo murine model of atherosclerosis were used to evaluate the mechanisms underlying metabolic and inflammatory activity of macrophages in the different atherosclerotic conditions analyzed. We observed that macrophage energetics and inflammatory activation are closely and linearly related, resulting in dynamic calibration of glycolysis to keep pace with inflammatory activity. Additionally, we show that macrophage glycolysis and proinflammatory activation mainly depend on hypoxia-inducible factor (HIF) and on its impact on glucose uptake, and on the expression of hexokinase II and ubiquitous 6-phosphofructo-2-kinase (PFKFB3). As a consequence, hypoxia potentiates inflammation and glycolysis mainly via these pathways. Moreover, when macrophages’ ability to increase glycolysis through PFKFB3 is experimentally attenuated, cell viability is reduced if subjected to proinflammatory and/or hypoxic conditions, but unaffected under control conditions. In addition to this, GM-CSF enhances anaerobic glycolysis while exerting a mild pro-inflammatory activation. These findings, in human and murine cells and in an animal model, show that hypoxia potentiates macrophage glycolytic flux in concert with a proportional up-regulation of pro-inflammatory activity, in a manner that is dependent on both HIF-1α and PFKFB3.