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

Haiyun Liu, Lei Huang, Jillian Bradley, Kebin Liu, Kankana Bardhan, David Ron, Andrew L. Mellor, David H. Munn, Tracy L. McGaha

Research output: Contribution to journalArticle

30 Citations (Scopus)

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 Tolllike 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.

Original languageEnglish (US)
Pages (from-to)428-438
Number of pages11
JournalMolecular and Cellular Biology
Volume34
Issue number3
DOIs
StatePublished - Feb 1 2014

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Physiological Stress
Lipopolysaccharides
Macrophages
Pathology
Cytokines
Amino Acids
Knockout Mice
Tryptophan
Interleukin-6
Indoleamine-Pyrrole 2,3,-Dioxygenase
Mortality
Interleukin-12
Heat-Shock Proteins
Sepsis
Phosphotransferases
Ligands
Inflammation
Gene Expression
Proteins

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

GCN2-dependent metabolic stress is essential for endotoxemic cytokine induction and pathology. / Liu, Haiyun; Huang, Lei; Bradley, Jillian; Liu, Kebin; Bardhan, Kankana; Ron, David; Mellor, Andrew L.; Munn, David H.; McGaha, Tracy L.

In: Molecular and Cellular Biology, Vol. 34, No. 3, 01.02.2014, p. 428-438.

Research output: Contribution to journalArticle

Liu, Haiyun ; Huang, Lei ; Bradley, Jillian ; Liu, Kebin ; Bardhan, Kankana ; Ron, David ; Mellor, Andrew L. ; Munn, David H. ; McGaha, Tracy L. / GCN2-dependent metabolic stress is essential for endotoxemic cytokine induction and pathology. In: Molecular and Cellular Biology. 2014 ; Vol. 34, No. 3. pp. 428-438.
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