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

Nat Immunol. 2015 Aug;16(8):838-849. doi: 10.1038/ni.3205. Epub 2015 Jun 29.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / immunology
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Blotting, Western
  • Cells, Cultured
  • Eukaryotic Initiation Factor-4E / genetics
  • Eukaryotic Initiation Factor-4E / immunology
  • Eukaryotic Initiation Factor-4E / metabolism
  • Gene Expression Profiling
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / immunology
  • Homeodomain Proteins / metabolism
  • Humans
  • 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
  • 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
  • RNA Interference
  • RNA, Messenger / genetics
  • RNA, Messenger / immunology*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Signal Transduction / immunology
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / immunology
  • TOR Serine-Threonine Kinases / metabolism
  • Toll-Like Receptor 2 / genetics
  • Toll-Like Receptor 2 / immunology
  • Toll-Like Receptor 2 / metabolism
  • Transcription Factor HES-1

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Eukaryotic Initiation Factor-4E
  • Homeodomain Proteins
  • Intracellular Signaling Peptides and Proteins
  • MicroRNAs
  • Multiprotein Complexes
  • RNA, Messenger
  • Toll-Like Receptor 2
  • Transcription Factor HES-1
  • HES1 protein, human
  • Interferon-gamma
  • MKNK1 protein, human
  • TOR Serine-Threonine Kinases
  • MKNK2 protein, human
  • Mechanistic Target of Rapamycin Complex 1
  • Protein-Serine-Threonine Kinases

Associated data

  • GEO/GSE66810