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

Author:

Liu Haiyun1,Huang Lei12,Bradley Jillian1,Liu Kebin13,Bardhan Kankana3,Ron David4,Mellor Andrew L.15,Munn David H.16,McGaha Tracy L.15

Affiliation:

1. Cancer Immunology, Inflammation, and Tolerance Program, GRU Cancer Center, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, USA

2. Department of Radiology, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, USA

3. Department of Biochemistry, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, USA

4. University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Center, Cambridge, United Kingdom

5. Department of Medicine, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, USA

6. Department of Pediatrics, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, USA

Abstract

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.

Publisher

American Society for Microbiology

Subject

Cell Biology,Molecular Biology

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