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GCN2-dependent metabolic stress is essential for endotoxemic cytokine induction and pathology

Lookup NU author(s): Emeritus Professor Andrew Mellor

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Abstract

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.


Publication metadata

Author(s): Liu H, Huang L, Bradley J, Liu K, Bardhan K, Ron D, Mellor AL, Munn DH, McGaha TL

Publication type: Article

Publication status: Published

Journal: Molecular and Cellular Biology

Year: 2014

Volume: 34

Issue: 3

Pages: 428-438

Print publication date: 01/02/2014

Online publication date: 18/11/2013

Acceptance date: 12/11/2013

ISSN (print): 0270-7306

ISSN (electronic): 1098-5549

Publisher: American Society for Microbiology

URL: http://dx.doi.org/10.1128/MCB.00946-13

DOI: 10.1128/MCB.00946-13

PubMed id: 24248597


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