Immunoresponsive gene 1 augments bactericidal activity of macrophage-lineage cells by regulating β-oxidation-dependent mitochondrial ROS production.
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.
Department of Molecular Medicine and Pathology, School of Medical Sciences, The University of Auckland, New Zealand.
Christopher J
CJ
Hall
Rachel H
RH
Boyle
Jonathan W
JW
Astin
Maria Vega
MV
Flores
Stefan H
SH
Oehlers
Leslie E
LE
Sanderson
Felix
F
Ellett
Graham J
GJ
Lieschke
Kathryn E
KE
Crosier
Philip S
PS
Crosier
D000818:Animals; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000096:biosynthesis / Q000378:metabolism; D002460:Cell Line; D005227:Fatty Acids / Q000378:metabolism; D005938:Glucocorticoids / Q000378:metabolism; D006836:Hydro-Lyases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D053612:Janus Kinases / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D060172:Morpholinos / Q000235:genetics; D010085:Oxidative Phosphorylation; D010587:Phagocytosis / Q000276:immunology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012480:Salmonella Infections / Q000276:immunology; D012486:Salmonella typhimurium / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D015027:Zebrafish / Q000276:immunology / Q000382:microbiology; D029961:Zebrafish Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*
D022782:CCAAT-Enhancer-Binding Protein-beta; C545013:Cebpb protein, mouse; D005227:Fatty Acids; D005938:Glucocorticoids; D008070:Lipopolysaccharides; D060172:Morpholinos; D017382:Reactive Oxygen Species; D029961:Zebrafish Proteins; D053612:Janus Kinases; D006836:Hydro-Lyases; C569511:Irg1L protein, zebrafish