Immunoresponsive gene 1 augments bactericidal activity of macrophage-lineage cells by regulating β-oxidation-dependent mitochondrial ROS production

Cell Metab. 2013 Aug 6;18(2):265-78. doi: 10.1016/j.cmet.2013.06.018.


Evidence suggests the bactericidal activity of mitochondria-derived reactive oxygen species (mROS) directly contributes to killing phagocytozed bacteria. Infection-responsive components that regulate this process remain incompletely understood. We describe a role for the mitochondria-localizing enzyme encoded by Immunoresponsive gene 1 (IRG1) during the utilization of fatty acids as a fuel for oxidative phosphorylation (OXPHOS) and associated mROS production. In a zebrafish infection model, infection-responsive expression of zebrafish irg1 is specific to macrophage-lineage cells and is regulated cooperatively by glucocorticoid and JAK/STAT signaling pathways. Irg1-depleted macrophage-lineage cells are impaired in their ability to utilize fatty acids as an energy substrate for OXPHOS-derived mROS production resulting in defective bactericidal activity. Additionally, the requirement for fatty acid β-oxidation during infection-responsive mROS production and bactericidal activity toward intracellular bacteria is conserved in murine macrophages. These results reveal IRG1 as a key component of the immunometabolism axis, connecting infection, cellular metabolism, and macrophage effector function.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CCAAT-Enhancer-Binding Protein-beta / biosynthesis
  • CCAAT-Enhancer-Binding Protein-beta / metabolism
  • Cell Line
  • Fatty Acids / metabolism
  • Glucocorticoids / metabolism
  • Hydro-Lyases / biosynthesis
  • Hydro-Lyases / genetics
  • Hydro-Lyases / metabolism*
  • Janus Kinases / metabolism
  • Lipopolysaccharides / immunology
  • Macrophages / immunology*
  • Mice
  • Mitochondria / metabolism*
  • Morpholinos / genetics
  • Oxidative Phosphorylation
  • Phagocytosis / immunology
  • Reactive Oxygen Species / metabolism*
  • Salmonella Infections / immunology
  • Salmonella typhimurium / immunology
  • Signal Transduction / immunology
  • Zebrafish / immunology
  • Zebrafish / microbiology
  • Zebrafish Proteins / biosynthesis
  • Zebrafish Proteins / genetics
  • Zebrafish Proteins / metabolism*


  • CCAAT-Enhancer-Binding Protein-beta
  • Cebpb protein, mouse
  • Fatty Acids
  • Glucocorticoids
  • Lipopolysaccharides
  • Morpholinos
  • Reactive Oxygen Species
  • Zebrafish Proteins
  • Janus Kinases
  • Hydro-Lyases
  • Irg1L protein, zebrafish