Immunoresponsive Gene 1 Augments Bactericidal Activity of Macrophage-Lineage Cells by Regulating β-Oxidation-Dependent Mitochondrial ROS Production
- Authors
- 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.
- ID
- ZDB-PUB-130903-8
- 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.