Liu H, Huang L, Bradley J, Liu K, Bardhan K, Ron D, Mellor AL, Munn DH, McGaha TL. GCN2 dependent metabolic stress is essential for cytokine induction and pathology in murine sepsis. Mol Cell Biol. 2013 Nov 18. [Epub ahead of print]
Activated inflammatory macrophages can express 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 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 TLR4 ligand lipopolysaccharide (LPS) with significantly increased IL-6 production. Tryptophan withdrawl induced the stress response proteins ATF4 and CHOP/GADD153; however LPS stimulation rapidly enhanced expression of both proteins. Moreover, LPS-driven cytokine production in amino acid deficient conditions was dependent on GCN2 as 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 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 amino acid depletion stress signals (via GCN2) synergize with pro-inflammatory signals to potently increase innate immune responsiveness.