Tan Zheng, Xie Na, Cui Huachun, Moellering Douglas R, Abraham Edward, Thannickal Victor J, Liu Gang
Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294; Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, China;
Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294;
J Immunol. 2015 Jun 15;194(12):6082-9. doi: 10.4049/jimmunol.1402469. Epub 2015 May 11.
The M1 and M2 polarized phenotypes dictate distinctive roles for macrophages as they participate in inflammatory disorders. There has been growing interest in the role of cellular metabolism in macrophage polarization. However, it is currently unclear whether different aspects of a specific metabolic program coordinately regulate this cellular process. In this study, we found that pyruvate dehydrogenase kinase 1 (PDK1), a key regulatory enzyme in glucose metabolism, plays an important role in the differential activation of macrophages. Knockdown of PDK1 diminished M1, whereas it enhanced M2 activation of macrophages. Mechanistically, PDK1 knockdown led to diminished aerobic glycolysis in M1 macrophages, which likely accounts for the attenuated inflammatory response in these cells. Furthermore, we found that mitochondrial respiration is enhanced during and required by the early activation of M2 macrophages. Suppression of glucose oxidation, but not that of fatty acids, inhibits this process. Consistent with its inhibitory role in early M2 activation, knockdown of PDK1 enhanced mitochondrial respiration in macrophages. Our data suggest that two arms of the glucose metabolism synergistically regulate the differential activation of macrophages. Our findings also highlight the central role of PDK1 in this event via controlling glycolysis and glucose oxidation.
M1和M2极化表型决定了巨噬细胞在参与炎症性疾病时的独特作用。细胞代谢在巨噬细胞极化中的作用越来越受到关注。然而，目前尚不清楚特定代谢程序的不同方面是否协同调节这一细胞过程。在本研究中，我们发现丙酮酸脱氢酶激酶1（PDK1）作为葡萄糖代谢中的关键调节酶，在巨噬细胞的差异激活中起重要作用。敲低PDK1会减少M1型巨噬细胞，而增强巨噬细胞的M2型激活。从机制上讲，敲低PDK1导致M1型巨噬细胞有氧糖酵解减少，这可能是这些细胞炎症反应减弱的原因。此外，我们发现M2型巨噬细胞早期激活过程中线粒体呼吸增强且是必需的。抑制葡萄糖氧化而非脂肪酸氧化可抑制这一过程。与PDK1在M2型巨噬细胞早期激活中的抑制作用一致，敲低PDK1可增强巨噬细胞的线粒体呼吸。我们的数据表明，葡萄糖代谢的两个分支协同调节巨噬细胞的差异激活。我们的研究结果还突出了PDK1通过控制糖酵解和葡萄糖氧化在这一过程中的核心作用。
