Glycolytic pathway affects differentiation of human monocytes to regulatory macrophages
Glycolytic pathway affects differentiation of human monocytes to regulatory macrophages
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DOI：
10.1016/j.imlet.2016.05.009
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发表时间：
2016-08-01
影响因子：
4.4
通讯作者：
Kanai, Takanori
中科院分区：
文献类型：
--
作者：
Suzuki, Hiroaki;Hisamatsu, Tadakazu;Kanai, Takanori
细胞代谢状态和单个代谢物已被报道调节免疫细胞的功能表型。调节性巨噬细胞和炎症性巨噬细胞产生的细胞因子被认为主要分别涉及脂肪酸氧化和糖酵解，这为线粒体氧化磷酸化提供燃料。然而，代谢途径和特定巨噬细胞表型的获得之间的关联仍然不清楚。本研究评估了糖酵解与调节性巨噬细胞分化之间的关系。在巨噬细胞集落刺激因子存在下体外培养来自外周血的人单核细胞以产生调节性巨噬细胞（M-M phi s）。M-M phi s具有调节性巨噬细胞表型，并在脂多糖刺激后产生大量IL-10。为了分析糖酵解的作用，在M-M phi分化期间加入糖酵解抑制剂（2-脱氧-D-葡萄糖或二氯乙酸盐）。与没有糖酵解抑制剂分化的M-M phi相比，用糖酵解抑制剂培养的这些细胞产生显著较低量的IL-10，但产生显著较高量的IL-6。糖酵解抑制剂诱导的M-M phi分化的这种表型变化与与巨噬细胞分化相关的基因表达模式的改变有关，如CSF 1、MMP 9和VEGFA。用糖酵解抑制剂分化的M-M phi似乎保留了成为IL-10产生细胞的可塑性。此外，发现培养基中丙酮酸水平的增加部分逆转了糖酵解抑制剂对M-M phi s细胞因子产生的影响。这些结果表明糖酵解途径在巨噬细胞分化为调节表型中的重要性，丙酮酸可能是这一过程中的关键代谢产物之一。(C)2016作者由Elsevier B. V.代表欧洲免疫学会联合会出版。
Cellular metabolic state and individual metabolites have been reported to regulate the functional phenotype of immune cells. Cytokine production by regulatory and inflammatory macrophages is thought to mainly involve fatty acid oxidation and glycolysis, respectively, which fuel mitochondrial oxidative phosphorylation. However, the association between metabolic pathways and the acquisition of specific macrophage phenotypes remains unclear. This study assessed the relationship between glycolysis and the differentiation of regulatory macrophages. Human monocytes derived from peripheral blood were cultured in vitro in the presence of macrophage colony-stimulating factor to yield regulatory macrophages (M-M phi s). M-M phi s had a regulatory macrophage phenotype and produced substantial IL-10 following stimulation with lipopolysaccharide. To analyze the role of glycolysis, glycolysis inhibitors (2-deoxy-D-glucose or dichloroacetate) were added during M-M phi differentiation. These cells cultured with glycolysis inhibitors produced significantly lower amounts of IL-10, but produced significantly higher amounts of IL-6 compared to M-M phi s differentiated without glycolysis inhibitors. Such phenotypic change of M-M phi s differentiated with glycolysis inhibitors was associated with the alteration of the gene expression pattern related to macrophage differentiation, such as CSF1, MMP9 and VEGFA. M-M phi s differentiated with glycolysis inhibitors seemed to retain plasticity to become IL-10 producing cells. Furthermore, increased level of pyruvate in culture medium was found to partially reverse the effects of glycolysis inhibitors on cytokine production of M-M phi s. These results indicate the importance of glycolytic pathway in macrophage differentiation to a regulatory phenotype, and pyruvate may be one of the key metabolites in this process. (C) 2016 The Authors. Published by Elsevier B.V. on behalf of European Federation of Immunological Societies.