title: GSTO1-1 modulates metabolism in macrophages activated through the LPS and TLR4 pathway.
abstract: Macrophages mediate innate immune responses that recognise foreign pathogens, and bacterial lipopolysaccharide (LPS) recruits a signalling pathway through Toll-like receptor 4 (TLR4) to induce pro-inflammatory cytokines and reactive oxygen species (ROS). LPS activation also skews the metabolism of macrophages towards a glycolytic phenotype. Here, we demonstrate that the LPS-triggered glycolytic switch is significantly attenuated in macrophages deficient for glutathione transferase omega-1 (GSTO1, note that GSTO1-1 refers to the dimeric molecule with identical type 1 subunits). In response to LPS, GSTO1-1-deficient macrophages do not produce excess lactate, or dephosphorylate AMPK, a key metabolic stress regulator. In addition, GSTO1-1-deficient cells do not induce HIF1α, which plays a key role in maintaining the pro-inflammatory state of activated macrophages. The accumulation of the TCA cycle intermediates succinate and fumarate that occurs in LPS-treated macrophages was also blocked in GSTO1-1-deficient cells. These data indicate that GSTO1-1 is required for LPS-mediated signalling in macrophages and that it acts early in the LPS-TLR4 pro-inflammatory pathway.
authors.affiliation: Department of Molecular Biosciences, John Curtin School of Medical Research, Australian National University, Canberra, ACT 2600, Australia.
authors.forename: Deepthi
authors.initials: D
authors.lastname: Menon
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, St Lucia 4072, Australia.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Coll
authors.affiliation: School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.
authors.forename: Luke A J
authors.initials: LA
authors.lastname: O'Neill
authors.affiliation: Department of Molecular Biosciences, John Curtin School of Medical Research, Australian National University, Canberra, ACT 2600, Australia Philip.Board@anu.edu.au.
authors.forename: Philip G
authors.initials: PG
authors.lastname: Board
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D005982:Glutathione Transferase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D051379:Mice; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; C117709:Gsto1 protein, mouse; D008070:Lipopolysaccharides; D017382:Reactive Oxygen Species; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D005982:Glutathione Transferase
keywords: GSTO1-1; LPS; Metabolism; Redox; TLR4