ZFIN ID: ZDB-PUB-130903-8
Immunoresponsive Gene 1 Augments Bactericidal Activity of Macrophage-Lineage Cells by Regulating β-Oxidation-Dependent Mitochondrial ROS Production
Hall, C.J., Boyle, R.H., Astin, J.W., Flores, M.V., Oehlers, S.H., Sanderson, L.E., Ellett, F., Lieschke, G.J., Crosier, K.E., and Crosier, P.S.
Date: 2013
Source: Cell Metabolism   18(2): 265-278 (Journal)
Registered Authors: Crosier, Kathy, Crosier, Phil, Ellett, Felix, Flores, Maria, Hall, Chris, Lieschke, Graham J., Oehlers, Stefan
Keywords: none
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*
PubMed: 23931757 Full text @ Cell Metab.

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.