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

Area of Science:

• Immunology
• Cell Biology
• Molecular Biology

Background:

• Interferon-gamma (IFN-γ) is crucial for activating macrophages against microbes.
• The impact of IFN-γ on macrophage metabolism and mRNA translation remains largely unexplored.
• Toll-like receptors (TLRs) mediate inflammatory responses in macrophages.

Purpose of the Study:

• To investigate how IFN-γ regulates human macrophage metabolism and mRNA translation.
• To identify the molecular pathways involved in IFN-γ-mediated macrophage priming.
• To understand the role of metabolic and translational control in classical inflammatory macrophage activation.

Main Methods:

• Human macrophages were treated with IFN-γ and stimulated with Toll-like receptors (TLRs).
• Kinase activity of mTORC1 and MNK was assessed.
• Genome-wide ribosome profiling was employed to analyze the macrophage translatome.
• Expression levels of specific genes like HES1 were measured.

Main Results:

• IFN-γ regulates macrophage metabolism and mRNA translation by targeting mTORC1 and MNK kinases.
• Downregulation of mTORC1 by IFN-γ is linked to autophagy and suppressed translation of inflammation repressors (e.g., HES1).
• IFN-γ selectively alters the macrophage translatome, promoting inflammation, metabolic reprogramming, and protein synthesis.

Conclusions:

• IFN-γ-mediated metabolic reprogramming and translational regulation are essential for classical inflammatory macrophage activation.
• Targeting mTORC1 and MNK kinases offers potential therapeutic avenues for modulating macrophage inflammatory responses.
• Understanding these mechanisms provides insights into host defense and inflammatory diseases.