Journal Article

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

Giannopoulou, Eugenia G, Ivashkiv, Lionel B, Hu, Xiaoyu, Yu, Yingpu, Liu, Hui, Rätsch, Gunnar, Su, Xiaodi, Rice, Charles M, Zhong, Yi, Cross, Justin R

2015

Overview

Interferon-γ (IFN-γ) primes macrophages to undergo proinflammatory activation. Ivashkiv and colleagues detail the translational and metabolic program triggered in human macrophages after IFN-γ treatment. Interferon-γ (IFN-γ) 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-γ 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 by IFN-γ was associated with autophagy and translational suppression of repressors of inflammation such as HES1. Genome-wide ribosome profiling in TLR2-stimulated macrophages showed that IFN-γ selectively modulated the macrophage translatome to promote inflammation, further reprogram metabolic pathways and modulate protein synthesis. These results show that IFN-γ–mediated metabolic reprogramming and translational regulation are key components of classical inflammatory macrophage activation.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 13 / 13/89 / 13/95 / 38/39 / 45/91 / 631/250/127/1212 / 82/1 / Analysis / Base Sequence / Basic Helix-Loop-Helix Transcription Factors - genetics / Basic Helix-Loop-Helix Transcription Factors - immunology / Basic Helix-Loop-Helix Transcription Factors - metabolism / Biomedicine / Blotting, Western / Cells, Cultured / Eukaryotic Initiation Factor-4E - genetics / Eukaryotic Initiation Factor-4E - immunology / Eukaryotic Initiation Factor-4E - metabolism / Gene Expression Profiling / Genetic transcription / Health aspects / Homeodomain Proteins - genetics / Homeodomain Proteins - immunology / Homeodomain Proteins - metabolism / Humans / Immune response / Immunology / Infectious Diseases / Interferon-gamma - immunology / Interferon-gamma - pharmacology / Intracellular Signaling Peptides and Proteins - genetics / Intracellular Signaling Peptides and Proteins - immunology / Intracellular Signaling Peptides and Proteins - metabolism / Macrophage Activation - drug effects / Macrophage Activation - genetics / Macrophage Activation - immunology / Macrophages - drug effects / Macrophages - immunology / Macrophages - metabolism / Mechanistic Target of Rapamycin Complex 1 / MicroRNA / MicroRNAs - genetics / Microscopy, Fluorescence / Multiprotein Complexes - genetics / Multiprotein Complexes - immunology / Multiprotein Complexes - metabolism / Protein Biosynthesis - drug effects / Protein Biosynthesis - genetics / Protein Biosynthesis - immunology / Protein-Serine-Threonine Kinases - genetics / Protein-Serine-Threonine Kinases - immunology / Protein-Serine-Threonine Kinases - metabolism / Rapamycin / Reverse Transcriptase Polymerase Chain Reaction / RNA Interference / RNA, Messenger - genetics / RNA, Messenger - immunology / Signal Transduction - drug effects / Signal Transduction - genetics / Signal Transduction - immunology / Stimuli (Psychology) / Toll-Like Receptor 2 - genetics / Toll-Like Receptor 2 - immunology / Toll-Like Receptor 2 - metabolism / TOR Serine-Threonine Kinases - genetics / TOR Serine-Threonine Kinases - immunology / TOR Serine-Threonine Kinases - metabolism / Transcription Factor HES-1