4.5 Article

GCN2-Dependent Metabolic Stress Is Essential for Endotoxemic Cytokine Induction and Pathology

Journal

MOLECULAR AND CELLULAR BIOLOGY
Volume 34, Issue 3, Pages 428-438

Publisher

AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.00946-13

Keywords

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Funding

  1. intramural grant from Georgia Regents University
  2. NIH/NIAID [AI092213]
  3. Wellcome Trust Principal Research Fellowship
  4. EU FP7 BetaBat grant [277713]

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Activated inflammatory macrophages can express indoleamine 2,3-dioxygenase (IDO) and thus actively deplete their own tryptophan supply; however, it is not clear how amino acid depletion influences macrophage behavior in inflammatory environments. In this report, we demonstrate that the stress response kinase GCN2 promotes macrophage inflammation and mortality in a mouse model of septicemia. In vitro, enzymatic amino acid consumption enhanced sensitivity of macrophages to the Toll-like receptor 4 (TLR4) ligand lipopolysaccharide (LPS) with significantly increased interleukin 6 (IL-6) production. Tryptophan withdrawal induced the stress response proteins ATF4 and CHOP/GADD153; however, LPS stimulation rapidly enhanced expression of both proteins. Moreover, LPS-driven cytokine production under amino acid-deficient conditions was dependent on GCN2, as GCN2 knockout (GCN2KO) macrophages had a significant reduction of cytokine gene expression after LPS stimulation. To test the in vivo relevance of these findings, monocytic-lineage-specific GCN2KO mice were challenged with a lethal dose of LPS intraperitoneally (i.p.). The GCN2KO mice showed reduced inflammatory responses, with decreased IL-6 and IL-12 expression correlating with significant reduction in animal mortality. Thus, the data show that amino acid depletion stress signals (via GCN2) synergize with proinflammatory signals to potently increase innate immune responsiveness.

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