Complete polarization of macrophages towards an M1-like proinflammatory and antimicrobial state requires combined action of IFN- and LPS. Synergistic activation of canonical inflammatory NF-B target genes by IFN- and LPS is well appreciated, but less is known about whether IFN- negatively regulates components of the LPS response, and how this affects polarization. A combined transcriptomic and epigenomic approach revealed that IFN- selectively abrogates LPS-induced feedback and select metabolic pathways by suppressing TLR4-mediated activation of gene enhancers. In contrast to superinduction of inflammatory genes via enhancers that harbor IRF sequences and bind STAT1, IFN--mediated repression targeted enhancers with STAT sequences that bound STAT3. TLR4-activated IFN--suppressed enhancers comprised two subsets distinguished by differential regulation of histone acetylation and recruitment of STAT3, CDK8 and cohesin, and were functionally inactivated by IFN-. These findings reveal that IFN- suppresses feedback inhibitory and metabolic components of the TLR response to achieve full M1 polarization, and provide insights into mechanisms by which IFN- selectively inhibits TLR4-induced transcription. SOURCE: Mahesh Bachu (bmahesh07@gmail.com) - SMGI Hospital For Special Surgery

Pluto Bioinformatics

GSE130567: IFN- selectively suppresses a subset of TLR4-activated genes and enhancers to potentiate M1-like macrophage polarization [RNA-seq II]