title: 3-bromopyruvate ameliorate autoimmune arthritis by modulating Th17/Treg cell differentiation and suppressing dendritic cell activation.
abstract: Recent studies have shown that cellular metabolism plays an important role in regulating immune cell functions. In immune cell differentiation, both interleukin-17-producing T (Th17) cells and dendritic cells (DCs) exhibit increased glycolysis through the upregulation of glycolytic enzymes, such as hexokinase-2 (HK2). Blocking glycolysis with 2-deoxyglucose was recently shown to inhibit Th17 cell differentiation while promoting regulatory T (Treg) cell generation. However, 2-DG inhibits all isoforms of HK. Thus, it is unclear which isoform has a critical role in Th17 cell differentiation and in rheumatoid arthritis (RA) pathogenesis. Here we demonstrated that 3-bromopyruvate (BrPA), a specific HK2 inhibitor, significantly decreased the arthritis scores and the histological scores in SKG mice, with a significant increase in Treg cells, decrease in Th17 cells, and decrease in activated DCs in the spleen. In vitro, BrPA facilitated the differentiation of Treg cells, suppressed Th17 cells, and inhibited the activation of DCs. These results suggested that BrPA may be a therapeutic target of murine arthritis. Although the role of IL-17 is not clarified in the treatment of RA, targeting cell metabolism to alter the immune cell functions might lead to a new therapeutic strategy for RA.
authors.affiliation: Rheumatology and Clinical Immunology, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Takaichi
authors.initials: T
authors.lastname: Okano
authors.affiliation: Department of Clinical Laboratory, Kobe University Hospital, Kobe, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Saegusa
authors.affiliation: Rheumatology and Clinical Immunology, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Nishimura
authors.affiliation: Rheumatology and Clinical Immunology, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Soshi
authors.initials: S
authors.lastname: Takahashi
authors.affiliation: Rheumatology and Clinical Immunology, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Sho
authors.initials: S
authors.lastname: Sendo
authors.affiliation: Rheumatology and Clinical Immunology, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Yo
authors.initials: Y
authors.lastname: Ueda
authors.affiliation: Rheumatology and Clinical Immunology, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Akio
authors.initials: A
authors.lastname: Morinobu
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D001327:Autoimmune Diseases / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D002454:Cell Differentiation / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D006593:Hexokinase / Q000235:genetics / Q000378:metabolism; D008213:Lymphocyte Activation; D018655:Lymphocyte Count; D051379:Mice; D011773:Pyruvates / Q000494:pharmacology*; D013583:Synovial Membrane / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D058504:Th17 Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism
chemical_list: D011773:Pyruvates; C017092:bromopyruvate; D006593:Hexokinase; C000598049:hexokinase 2, mouse