Reshaping of Human Macrophage Polarization through Modulation of Glucose Catabolic Pathways
Reshaping of Human Macrophage Polarization through Modulation of Glucose Catabolic Pathways
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DOI：
10.4049/jimmunol.1403045
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发表时间：
2015-09-01
影响因子：
4.4
通讯作者：
Escribese, Maria M.
中科院分区：
文献类型：
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作者：
Izquierdo, Elena;Delgado Cuevas, Victor;Escribese, Maria M.
巨噬细胞整合来自组织微环境的信息，并根据普遍的细胞外刺激调节其效应器功能。因此，巨噬细胞可以获得各种激活（极化）状态，这种功能可塑性允许炎症反应的充分启动，调节和解决。葡萄糖代谢的调节有助于巨噬细胞适应周围的细胞因子环境，如暴露于LPS/IFN-γ或IL-4的巨噬细胞的不同葡萄糖催化剂所例示的。为了剖析在不存在活化细胞因子的情况下巨噬细胞效应子功能的获得，我们评估了在GM-CSF（GM-MO）或M-CSF（M-MO）存在下产生的巨噬细胞的生物能量谱，所述巨噬细胞不释放促炎或抗炎细胞因子，除非经受额外的活化刺激。与M-MO相比，GM-MO表现出更高的耗氧速率和有氧糖酵解（胞外酸化速率[ECAR]），以及编码糖酵解酶的基因的更高表达。然而，M-MO表现出显著更高的耗氧率/ECAR比。令人惊讶的是，有氧糖酵解正调控两种巨噬细胞亚型中的IL 1B、TNF和INHBA mRNA表达，而线粒体呼吸负影响M-MO中的IL 6、IL 1B、TNF和CXCL 10 mRNA表达。这些结果的生理意义在低氧张力下变得明显，因为低氧通过HIF-1 α和HIF-2 α增强M-MO中的ECAR，增加糖酵解酶和GM-MO特异性基因的表达，并减少M-MO相关基因的表达。因此，我们的数据表明，GM-MO和M-MO显示出不同的生物能谱，缺氧通过促进ECAR中HIF-1 α/HIF-2 α依赖性增加而触发巨噬细胞中的转录组转换。
Macrophages integrate information from the tissue microenvironment and adjust their effector functions according to the prevalent extracellular stimuli. Therefore, macrophages can acquire a variety of activation (polarization) states, and this functional plasticity allows the adequate initiation, regulation, and resolution of inflammatory responses. Modulation of the glucose metabolism contributes to the macrophage adaptation to the surrounding cytokine milieu, as exemplified by the distinct glucose catabolism of macrophages exposed to LPS/IFN-gamma or IL-4. To dissect the acquisition of macrophage effector functions in the absence of activating cytokines, we assessed the bioenergetic profile of macrophages generated in the presence of GM-CSF (GM-MO) or M-CSF (M-MO), which do not release pro-or anti-inflammatory cytokines unless subjected to additional activating stimuli. Compared to M-MO, GM-MO displayed higher oxygen consumption rate and aerobic glycolysis (extracellular acidification rate [ECAR]), as well as higher expression of genes encoding glycolytic enzymes. However, M-MO exhibited a significantly higher oxygen consumption rate/ECAR ratio. Surprisingly, whereas aerobic glycolysis positively regulated IL1B, TNF, and INHBA mRNA expression in both macrophage subtypes, mitochondrial respiration negatively affected IL6, IL1B, TNF, and CXCL10 mRNA expression in M-MO. The physiological significance of these results became evident under low oxygen tensions, as hypoxia enhanced ECAR in M-MO via HIF-1 alpha and HIF-2 alpha, increased expression of glycolytic enzymes and GM-MO-specific genes, and diminished expression of M-MO-associated genes. Therefore, our data indicate that GM-MO and M-MO display distinct bioenergetic profiles, and that hypoxia triggers a transcriptomic switch in macrophages by promoting a HIF-1 alpha/HIF-2 alpha-dependent increase in ECAR.