Pyruvate Dehydrogenase Kinase Is a Metabolic Checkpoint for Polarization of Macrophages to the M1 Phenotype
Pyruvate Dehydrogenase Kinase Is a Metabolic Checkpoint for Polarization of Macrophages to the M1 Phenotype
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DOI：
10.3389/fimmu.2019.00944
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发表时间：
2019-05-07
影响因子：
7.3
通讯作者：
Lee, In-Kyu
中科院分区：
文献类型：
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作者：
Min, Byong-Keol;Park, Sungmi;Lee, In-Kyu
巨噬细胞极化过程中的代谢重编程支持这些细胞在健康和疾病中的效应功能。在这里，我们证明了丙酮酸脱氢酶激酶（PDK）可以抑制丙酮酸脱氢酶介导的细胞质丙酮酸向线粒体乙酰辅酶a的转化，在M1巨噬细胞中起代谢检查点的作用。PDK2和PDK4的缺失均不能阻止极化，但PDK2和PDK4的联合缺失可以完全阻止极化；这种极化的缺乏与线粒体呼吸的改善和代谢断裂的重新布线有关，代谢断裂的特征是糖酵解中间体的增加和TCA循环中代谢物的减少。基因缺失或药理抑制PDK2/4可防止巨噬细胞在炎症刺激（脂多糖加ifn - γ）下向M1表型极化。将pdk2 /4缺陷的骨髓移植到受辐照的野生型小鼠中，产生pdk2 /4缺陷骨髓细胞的小鼠，可以防止M1极化，减少肥胖相关的胰岛素抵抗，并改善脂肪组织炎症。一种新型的药理学PDK抑制剂KPLH1130可改善高脂肪饮食诱导的胰岛素抵抗；这与促炎标志物水平的降低和线粒体功能的改善有关。这些研究发现PDK2/4是巨噬细胞M1表型极化的代谢检查点，可能被开发为肥胖相关代谢紊乱和其他炎症疾病的新治疗靶点。
Metabolic reprogramming during macrophage polarization supports the effector functions of these cells in health and disease. Here, we demonstrate that pyruvate dehydrogenase kinase (PDK), which inhibits the pyruvate dehydrogenase-mediated conversion of cytosolic pyruvate to mitochondrial acetyl-CoA, functions as a metabolic checkpoint in M1 macrophages. Polarization was not prevented by PDK2 or PDK4 deletion but was fully prevented by the combined deletion of PDK2 and PDK4; this lack of polarization was correlated with improved mitochondrial respiration and rewiring of metabolic breaks that are characterized by increased glycolytic intermediates and reduced metabolites in the TCA cycle. Genetic deletion or pharmacological inhibition of PDK2/4 prevents polarization of macrophages to the M1 phenotype in response to inflammatory stimuli (lipopolysaccharide plus IFN-gamma). Transplantation of PDK2/4-deficient bone marrow into irradiated wild-type mice to produce mice with PDK2/4-deficient myeloid cells prevented M1 polarization, reduced obesity-associated insulin resistance, and ameliorated adipose tissue inflammation. A novel, pharmacological PDK inhibitor, KPLH1130, improved high-fat diet-induced insulin resistance; this was correlated with a reduction in the levels of pro-inflammatory markers and improved mitochondrial function. These studies identify PDK2/4 as a metabolic checkpoint for M1 phenotype polarization of macrophages, which could potentially be exploited as a novel therapeutic target for obesity-associated metabolic disorders and other inflammatory conditions.