IFN-? selectively suppresses a subset of TLR4-activated genes and enhancers to potentiate macrophage activation.

ABSTRACT: Activation of macrophage proinflammatory and antimicrobial phenotypes is regulated by IFN-? and LPS via synergistic induction of canonical, inflammatory NF-?B target genes. However, whether IFN-? 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-? 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-? represses target enhancers that bind STAT3. TLR4-activated but IFN-?-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-? suppresses feedback inhibitory and metabolic components of TLR responses to enhance macrophage activation; they also provide insights for IFN-?-mediated selective inhibition of TLR4-induced transcription. Such inhibition can contribute to severe and sustained inflammatory responses.

SUBMITTER: Kang K 

PROVIDER: S-EPMC6658531 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature