Epigenomic regulation of macrophage polarization: Where do the nuclear receptors belong?

Abstract

Our laboratory has a long-standing research interest in understanding how lipid-activated transcription factors, nuclear hormone receptors, contribute to dendritic cell and macrophage gene expression regulation, subtype specification, and responses to a changing extra and intracellular milieu. This journey in the last more than two decades took us from identifying target genes for various RXR heterodimers to systematically mapping nuclear receptor-mediated pathways in dendritic cells to identifying hierarchies of transcription factors in alternative polarization in macrophages to broaden the role of nuclear receptors beyond strictly ligand-regulated gene expression. We detail here the milestones of the road traveled and draw conclusions regarding the unexpectedly broad role of nuclear hormone receptors as epigenomic components of dendritic cell and macrophage gene regulation as we are getting ready for the next challenges.

Keywords: EGR2; IL-4; PPARγ; STAT6; epigenome; macrophage; nuclear receptors; polarization; transcriptional regulation.

Figure 1.

General scheme of signal response and integration in macrophages.

Figure 2.

The classical ligand-dependent regulatory role of RXR/PPARγ, RXR/LXR, RXR/RAR heterodimers, and RXR/RXR homodimers in macrophage biology and the proposed RXR-mediated enhancer promoter interaction of the Vegfa gene.

Figure 3.

The STAT6-EGR2 transcription factor axis-induced PPARγ expression during IL-4-mediated alternative macrophage polarization in murine BMDMs.

Figure 4.

The ligand-independent epigenomic ratchet activity of PPARγ leads to transcriptional memory and enhanced gene-specific responsiveness to IL-4 re-stimulation in alternatively polarized macrophages.

Figure 5.

The direct transcriptional repressor activity of STAT6 at a specific subset of inflammatory enhancers limits the inflammatory responsiveness in the alternatively polarized macrophages resulting in blunted inflammasome activation and pyroptosis.

Figure 6.

The IL-4-induced EGR2 and PPARγ transcription factors contribute to the gene subset-specific enhanced responsiveness to various environmental signals, including pathogen-derived molecules and nuclear receptor ligands, in the alternatively polarized macrophages.

Figure 7.

The potential connection between the phenomenon of extended synergism between IL4 and TLR signaling and the RXR signaling pathway in the alternatively polarized macrophages. (A) Partial overlap is observed between the LPS-activated de novo/enhanced NF-kB-p65 binding and the RXR cistrome at the synergistically activated enhancers in the alternatively polarized macrophages. Venn diagrams showing the overlap of RXR peaks with de novo and enhanced NFkB-p65 genomic regions (B) Read distribution plot visualization of NF-kB-p65 (purple), RNAPII-pS2 (red), and RXR (blue) binding at the de novo/enhanced NF-kB-p65 and RXR co-binding-associated synergistically activated enhancers (+/−2.5 kb from peak summits).

Figure 8.

Both ligand-dependent and ligand-insensitive epigenomic regulatory roles of nuclear hormone receptors modulate the macrophage responsiveness to various microenvironmental signals at the transcriptional level.