title: Glycolytic pathway affects differentiation of human monocytes to regulatory macrophages.
abstract: 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-Mϕs). M-Mϕs 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-Mϕ 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-Mϕs differentiated without glycolysis inhibitors. Such phenotypic change of M-Mϕs 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-Mϕs 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-Mϕs. 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.
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan; Research Institute, Ajinomoto Pharmaceuticals Co. Ltd., Kanagawa, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Suzuki
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan; Division of Gastroenterology and Hepatology, The Third Department of Internal Medicine, Kyorin University School of Medicine, Tokyo, Japan. Electronic address: thisamatsu@ks.kyorin-u.ac.jp.
authors.forename: Tadakazu
authors.initials: T
authors.lastname: Hisamatsu
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Sayako
authors.initials: S
authors.lastname: Chiba
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Kiyoto
authors.initials: K
authors.lastname: Mori
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Mina T
authors.initials: MT
authors.lastname: Kitazume
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Katsuyoshi
authors.initials: K
authors.lastname: Shimamura
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Nakamoto
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Katsuyoshi
authors.initials: K
authors.lastname: Matsuoka
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Hirotoshi
authors.initials: H
authors.lastname: Ebinuma
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Naganuma
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Takanori
authors.initials: T
authors.lastname: Kanai
mesh_terms: D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D003115:Colony-Stimulating Factors / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D005947:Glucose / Q000037:antagonists & inhibitors / Q000494:pharmacology; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D056747:Immunomodulation; D016753:Interleukin-10 / Q000378:metabolism; D008264:Macrophages / Q000276:immunology*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics; D009000:Monocytes / Q000187:drug effects / Q000276:immunology*; D019289:Pyruvic Acid / Q000378:metabolism*; D059467:Transcriptome; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
chemical_list: C115456:2-deoxy-glucose tetraacetate; D003115:Colony-Stimulating Factors; D016207:Cytokines; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D016753:Interleukin-10; D019289:Pyruvic Acid; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9; D005947:Glucose
keywords: Differentiation; Glycolytic pathway; Human monocyte; Regulatory macrophage