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

Deepthi Menon, Rebecca Coll, Luke A.J. O'Neill, Philip G. Board*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

36 Citations (Scopus)

Abstract

Macrophagesmediate 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 ofmacrophages 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 inLPS-treatedmacrophageswas also blocked inGSTO1-1-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.

Original languageEnglish
Pages (from-to)1982-1990
Number of pages9
JournalJournal of Cell Science
Volume128
Issue number10
DOIs
Publication statusPublished - 01 Jan 2015
Externally publishedYes

Keywords

  • GSTO1-1
  • LPS
  • Metabolism
  • Redox
  • TLR4

ASJC Scopus subject areas

  • Cell Biology

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