Interferon-gamma regulates cellular metabolism and mRNA translation to potentiate macrophage activation

Interferon-gamma (IFN-gamma) primes macrophages for enhanced microbial killing and inflammatory activation by Toll-like receptors (TLRs), but little is known about the regulation of cell metabolism or mRNA translation during this priming. We found that IFN-gamma regulated the metabolism and mRNA translation of human macrophages by targeting the kinases mTORC1 and MNK, both of which converge on the selective regulator of translation initiation eIF4E. Physiological downregulation of mTORC1 byIFN-gamma was associated with autophagy and translational suppression of repressors of inflammation such as HES1. Genome-wide ribosome profiling in TLR2-stimulated macrophages showed thatIFN-gamma selectively modulated the macrophage translatome to promote inflammation, further reprogram metabolic pathways and modulate protein synthesis. These results show thatIFN-gamma-mediated metabolic reprogramming and translational regulation are key components of classical inflammatory macrophage activation.