Immunoresponsive Gene 1 Augments Bactericidal Activity of Macrophage-Lineage Cells by Regulating β-Oxidation-Dependent Mitochondrial ROS Production

• DOI: 10.1016/j.cmet.2013.06.018
• Publication Date: 2013-08-06T23:47:03Z
• Authors: Christopher J. Hall; Rachel H. Boyle; Jonathan W. Astin; Maria Vega Flores; Stefan H. Oehlers; Leslie E. Sanderson; Felix Ellett; Graham J. Lieschke; Kathryn E. Crosier; Philip S. Crosier
• Keywords: Lipopolysaccharides; Salmonella typhimurium; 0301 basic medicine; Physiology; Oxidative Phosphorylation; Cell Line; Morpholinos; Mice; 03 medical and health sciences; Phagocytosis; Animals; Molecular Biology; Glucocorticoids; Hydro-Lyases; Zebrafish; Janus Kinases; CCAAT-Enhancer-Binding Protein-beta; Macrophages; Fatty Acids; Cell Biology; Zebrafish Proteins; Mitochondria; 3. Good health; Salmonella Infections; Reactive Oxygen Species; Signal Transduction

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.