HIF-1α-PDK1 axis-induced active glycolysis plays an essential role in macrophage migratory capacity.
HIF-1α-PDK1 axis-induced active glycolysis plays an essential role in macrophage migratory capacity.
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DOI：
10.1038/ncomms11635
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发表时间：
2016-05-18
影响因子：
16.6
通讯作者：
Komuro I
中科院分区：
文献类型：
--
作者：
Semba H;Takeda N;Isagawa T;Sugiura Y;Honda K;Wake M;Miyazawa H;Yamaguchi Y;Miura M;Jenkins DM;Choi H;Kim JW;Asagiri M;Cowburn AS;Abe H;Soma K;Koyama K;Katoh M;Sayama K;Goda N;Johnson RS;Manabe I;Nagai R;Komuro I
在严重缺氧条件下，发现HIF-1α介导的Pdk 1诱导通过阻止丙酮酸进入三羧酸循环来调节葡萄糖氧化。然而，单核细胞衍生的巨噬细胞在炎症区域的迁移过程中遇到氧可用性的逐渐减少。在这里，我们表明HIF-1α-PDK 1介导的代谢变化发生在轻度缺氧中，其中线粒体细胞色素c氧化酶活性未受损，这表明存在糖酵解重编程模式。在原代巨噬细胞中，PKM 2是一种负责糖酵解ATP合成的糖酵解酶，定位于丝状伪足和板状伪足中，在肌动蛋白重塑过程中ATP被快速消耗。值得注意的是，用二氯乙酸盐抑制糖酵解重编程显著损害体外和体内巨噬细胞迁移。此外，抑制巨噬细胞HIF-1α-PDK 1轴可抑制全身性炎症，这表明了一种调节炎症过程的潜在治疗方法。因此，我们的研究结果表明，葡萄糖代谢的适应性反应有助于巨噬细胞的迁移活动。 迁移到发炎组织需要在日益缺氧的环境中产生能量。在这里，作者表明，在迁移过程中，HIF 1 α诱导的PDK 1通过促进糖酵解同时保持细胞色素c氧化酶活性，独特地使巨噬细胞代谢适应轻度缺氧。
In severely hypoxic condition, HIF-1α-mediated induction of Pdk1 was found to regulate glucose oxidation by preventing the entry of pyruvate into the tricarboxylic cycle. Monocyte-derived macrophages, however, encounter a gradual decrease in oxygen availability during its migration process in inflammatory areas. Here we show that HIF-1α-PDK1-mediated metabolic changes occur in mild hypoxia, where mitochondrial cytochrome c oxidase activity is unimpaired, suggesting a mode of glycolytic reprogramming. In primary macrophages, PKM2, a glycolytic enzyme responsible for glycolytic ATP synthesis localizes in filopodia and lammelipodia, where ATP is rapidly consumed during actin remodelling processes. Remarkably, inhibition of glycolytic reprogramming with dichloroacetate significantly impairs macrophage migration in vitro and in vivo. Furthermore, inhibition of the macrophage HIF-1α-PDK1 axis suppresses systemic inflammation, suggesting a potential therapeutic approach for regulating inflammatory processes. Our findings thus demonstrate that adaptive responses in glucose metabolism contribute to macrophage migratory activity. Migration to the inflamed tissue demands energy production in an increasingly hypoxic environment. Here the authors show that during migration, HIF1α-induced PDK1 uniquely adapts macrophage metabolism to mild hypoxia by promoting glycolysis while preserving cytochrome c oxidase activity.