IFN-γ selectively suppresses a subset of TLR4-activated genes and enhancers to potentiate macrophage activation. Academic Article uri icon

Overview

abstract

  • Activation of macrophage proinflammatory and antimicrobial phenotypes is regulated by IFN-γ and LPS via synergistic induction of canonical, inflammatory NF-κB target genes. However, whether IFN-γ negatively regulates components of the LPS response, and how this may affect macrophage activation, is still unclear. Here we use combined transcriptomic and epigenomic approaches to find that IFN-γ selectively abrogates LPS-induced feedback and alters macrophage metabolic pathways by suppressing TLR4-mediated gene activation. In contrast to superinduction of inflammatory genes via enhancers that bind IRF1 and STAT1, IFN-γ represses target enhancers that bind STAT3. TLR4-activated but IFN-γ-suppressed enhancers comprise two subsets discernable by differential regulation of histone acetylation and recruitment of STAT3, CDK8 and cohesin. Our findings thus show that IFN-γ suppresses feedback inhibitory and metabolic components of TLR responses to enhance macrophage activation; they also provide insights for IFN-γ-mediated selective inhibition of TLR4-induced transcription. Such inhibition can contribute to severe and sustained inflammatory responses.

publication date

  • July 25, 2019

Research

keywords

  • Interferon-gamma
  • Macrophages
  • Toll-Like Receptor 4

Identity

PubMed Central ID

  • PMC6658531

Scopus Document Identifier

  • 85070672913

Digital Object Identifier (DOI)

  • 10.1038/nmeth.2688

PubMed ID

  • 31346169

Additional Document Info

volume

  • 10

issue

  • 1