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

Chris J Hall, Rachel H Boyle, Jonathan W Astin, Maria V Flores, Stefan Oehlers, Leslie E Sanderson, Felix Ellett, Graham Lieschke, Kathryn E Crosier, Philip S Crosier

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108 Citations (Scopus)

Abstract

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 beta-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.
Original languageEnglish
Pages (from-to)265 - 276
Number of pages12
JournalCell Metabolism
Volume18
Issue number2
DOIs
Publication statusPublished - 2013

Cite this

Hall, Chris J ; Boyle, Rachel H ; Astin, Jonathan W ; Flores, Maria V ; Oehlers, Stefan ; Sanderson, Leslie E ; Ellett, Felix ; Lieschke, Graham ; Crosier, Kathryn E ; Crosier, Philip S. / Immunoresponsive gene 1 augments bactericidal activity of macrophage-lineage cells by regulating beta-oxidation-dependent mitochondrial ROS production. In: Cell Metabolism. 2013 ; Vol. 18, No. 2. pp. 265 - 276.
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abstract = "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 beta-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.",
author = "Hall, {Chris J} and Boyle, {Rachel H} and Astin, {Jonathan W} and Flores, {Maria V} and Stefan Oehlers and Sanderson, {Leslie E} and Felix Ellett and Graham Lieschke and Crosier, {Kathryn E} and Crosier, {Philip S}",
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Hall, CJ, Boyle, RH, Astin, JW, Flores, MV, Oehlers, S, Sanderson, LE, Ellett, F, Lieschke, G, Crosier, KE & Crosier, PS 2013, 'Immunoresponsive gene 1 augments bactericidal activity of macrophage-lineage cells by regulating beta-oxidation-dependent mitochondrial ROS production', Cell Metabolism, vol. 18, no. 2, pp. 265 - 276. https://doi.org/10.1016/j.cmet.2013.06.018

Immunoresponsive gene 1 augments bactericidal activity of macrophage-lineage cells by regulating beta-oxidation-dependent mitochondrial ROS production. / Hall, Chris J; Boyle, Rachel H; Astin, Jonathan W; Flores, Maria V; Oehlers, Stefan; Sanderson, Leslie E; Ellett, Felix; Lieschke, Graham; Crosier, Kathryn E; Crosier, Philip S.

In: Cell Metabolism, Vol. 18, No. 2, 2013, p. 265 - 276.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Hall, Chris J

AU - Boyle, Rachel H

AU - Astin, Jonathan W

AU - Flores, Maria V

AU - Oehlers, Stefan

AU - Sanderson, Leslie E

AU - Ellett, Felix

AU - Lieschke, Graham

AU - Crosier, Kathryn E

AU - Crosier, Philip S

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AB - 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 beta-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.

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