Epigenetic regulation of macrophage polarization and function

Abstract

Macrophage polarization refers to development of a specific phenotype important for tissue homeostasis or host defense in response to environmental cues. Environmental factors that induce macrophage polarization include cytokines and microbial factors produced by pathogens or commensal microbiota. Signaling pathways utilized by these polarizing factors have been well characterized, but it is less clear how signals are converted into complex and sustained patterns of gene expression, and how macrophages are reprogrammed during polarization to alter their responses to subsequent environmental challenges. Emerging evidence, reviewed here, suggests an important role for epigenetic mechanisms in modulating and transmitting signals during macrophage polarization and reprogramming. Deeper understanding of epigenetic regulation of macrophage phenotype will enable development of gene-specific therapeutic approaches to enhance host defense while preserving tissue integrity and preventing chronic inflammatory diseases.

Figure 1

Epigenetic regulation of inflammatory cytokine gene loci in macrophages. (a) In cells that do not express inflammatory cytokines, corresponding gene loci exhibit inaccessible chromatin, occupancy by transcriptional repressors and corepressors (co-R), and negative histone marks. (b) During macrophage differentiation master transcription factors (also termed pioneer factors) such as Pu1 bind to cytokine gene promoters and enhancers and facilitate the opening of chromatin (as determined by DNase I hypersensitivity) by nucleosome remodeling and histone acetylation, and promote positive methyl marks (H3K4me3 at promoters and H3K4me1 at enhancers). Genes are maintained in a poised state of low or nonproductive basal transcription but high responsiveness to extracellular stimuli by a balance between positive and negative epigenetic marks. (c) Stimulation of macrophages by Toll-like receptor (TLR) ligands leads to release of corepressors, increased histone acetylation, additional nucleosome remodeling by Brahma-related gene (Brg)1 (as determined by restriction enzyme accessibility assays), and recruitment of signaling transcription factors (sTFs) such as nuclear factor (NF)-κB. This results in increased recruitment of general transcription factors (GTFs) and RNA polymerase II (pol II), and active transcription. Enhancers of active genes are characterized by occupancy by p300, H3K27-Ac, and low levels of transcription of noncoding enhancer RNA. (d) Mechanisms by which inflammatory genes are deactivated are not well understood, but include occupancy by transcriptional repressors (rTFs), decreases in histone acetylation mediated by histone deacetylases (HDACs), and nucleosome remodeling by the nucleosome remodeling and deacetylation (NURD) complex that also contains HDACs. This figure represents a composite; regulation of individual genes varies and gene-specific mechanisms are not depicted.