Opposing macrophage polarization programs show extensive epigenomic and transcriptional cross-talk

Abstract

Macrophage stimulation with interferon-γ (IFN-γ) and interleukin 4 (IL-4) triggers distinct and opposing activation programs. During mixed infections or cancer macrophages are often exposed to both cytokines, but how these two programs influence each other remains unclear. We found that IFN-γ and IL-4 mutually inhibited epigenomic and transcriptional changes induced by each cytokine alone. Computational and functional analyses revealed the genomic bases for gene-specific cross-repression. For instance, while STAT1 and IRF1 motifs were associated with robust and IL-4-resistant responses to IFN-γ their coexistence with binding sites for auxiliary transcription factors such as AP-1, generated vulnerability to IL-4-mediated inhibition. These data provide a core mechanistic framework for the integration of signals that control macrophage activation in complex environmental conditions.

Interferon-γ Represses M2 Gene Expression in Human Macrophages by Disassembling Enhancers Bound by the Transcription Factor MAF

“…This M2-like function of MAF in macrophages is consonant with its function in promoting IL-4 and IL-10 expression in T cells, and with a previous report implicating MAF in Il10 induction in mouse macrophages (Cao et al, 2002). This finding is also in line with a recent report that the MAF motif is enriched in a panel of IL-4-induced enhancers that were sensitive to inhibition by IFN-γ (Piccolo et al, 2017). Notably, MAF binding was most closely associated with enhancers that were disassembled after IFN-γ stimulation, and thus MAF occupancy can serve as a ‘mark’ for enhancers that are targeted by IFN-γ.…”

“…In addition, IFN-γ can prime macrophages for enhanced inflammatory responses by modulating chromatin at cis -regulatory regions of inflammatory genes (Chen and Ivashkiv, 2010), metabolic reprogramming (Cheng et al, 2016; Su et al, 2015), modulation of mRNA translation (Su et al, 2015), and antagonism of interleukin (IL)-4 (Piccolo et al, 2017). In contrast to IFN-γ-induced gene activation, mechanisms of IFN-γ- mediated suppression of gene expression and its functional consequences are poorly understood.…”

Transcriptional repression in macrophages—basic mechanisms and alterations in metabolic inflammatory diseases

“…Indeed, following exposure to Schistosoma mansoni eggs, an in vivo model of Th2 cytokine‐mediated disease that is limited by M2 macrophages, lung inflammation was improved in mice lacking HDAC3 in macrophages. Overall, the involvement of the HDAC3 in both M1 and M2 macrophage pathways points at a perhaps integrative role of the corepressor complex in mediating the documented extensive epigenomic and transcriptomic cross‐talk between these pathways .…”

Metabolic and Epigenetic Coordination of T Cell and Macrophage Immunity

“…In addition, metabolic reprogramming has also recently been proposed to involve a mammalian target of rapamycin complex 2 (mTORC2)-IRF4 signaling axis (Huang et al 2016). As with LPS treatment, responses to IL-4 are associated with extensive alterations of the epigenetic landscapes (Piccolo et al 2017). Intriguingly, IFNγ and IL-4 were found to mutually inhibit the epigenomic and transcriptional changes induced by each cytokine alone (Piccolo et al 2017).…”

“…As with LPS treatment, responses to IL-4 are associated with extensive alterations of the epigenetic landscapes (Piccolo et al 2017). Intriguingly, IFNγ and IL-4 were found to mutually inhibit the epigenomic and transcriptional changes induced by each cytokine alone (Piccolo et al 2017). …”