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      GSTO1-1 modulates metabolism in macrophages activated through the LPS and TLR4 pathway.

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          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.

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          Author and article information

          Journal
          J. Cell. Sci.
          Journal of cell science
          The Company of Biologists
          1477-9137
          0021-9533
          May 15 2015
          : 128
          : 10
          Affiliations
          [1 ] Department of Molecular Biosciences, John Curtin School of Medical Research, Australian National University, Canberra, ACT 2600, Australia.
          [2 ] Institute for Molecular Bioscience, The University of Queensland, St Lucia 4072, Australia.
          [3 ] School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.
          [4 ] Department of Molecular Biosciences, John Curtin School of Medical Research, Australian National University, Canberra, ACT 2600, Australia Philip.Board@anu.edu.au.
          Article
          jcs.167858
          10.1242/jcs.167858
          25908843
          137333cd-ff3f-4534-98ea-544c1a3a4115
          History

          GSTO1-1,LPS,Metabolism,Redox,TLR4
          GSTO1-1, LPS, Metabolism, Redox, TLR4

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