Molecular control of activation and priming in macrophages

Abstract

In tissues, macrophages are exposed to metabolic, homeostatic and immunoregulatory signals of local or systemic origin that influence their basal functions and responses to danger signals. Signal-transduction pathways regulated by extracellular signals are coupled to distinct sets of broadly expressed stimulus-regulated transcription factors whose ability to elicit gene-expression changes is influenced by the accessibility of their binding sites in the macrophage genome. In turn, accessibility of macrophage-specific transcriptional regulatory elements (enhancers and promoters) is specified by transcription factors that determine the macrophage lineage or impose their tissue-specific properties. Here we review recent findings that advance the understanding of mechanisms underlying priming and signal-dependent activation of macrophages and discuss the effect of genetic variation on these processes.

Figure 1

The interplay between homeostatic tissue signals and danger signals in the control of macrophage function. Tissue macrophages are exposed to micro-environmental signals that impact their gene expression programs and function and also affect the quality of their response to danger signals, resulting in distinct inflammatory gene expression programs in different tissues.

Figure 2

Three main groups of receptors relevant for macrophage activation were schematically classified based on the main transcription factors coupled to them. The coupling to the IRF3 transcription factor is critical for the activation of the Ifnb1 gene and the ensuing interferon response, which accounts for most of the secondary gene expression in macrophages activated by LPS.

Figure 3

Stimulus-regulated transcription factors (SRTFs) act at promoters and enhancers to direct broad or cell restricted transcriptional responses. Promoters and enhancers are primed by lineage-determining transcription factors (LDTFs) that collaborate with each other and other transcription factors to displace nucleosomes. Promoters, which are distinguished by high levels of H3K4me3 in comparison to H3K4me1, are generally primed in many cell types by broadly expressed transcription factors. Enhancers, which are distinguished by high levels of H3K4me1 in comparison to H3K4me3, are more likely to be primed by cell-type specific combinations of lineage determining transcription factors. PU.1, C/EBPs, AP-1 factors and IRFs are important macrophage lineage determining factors that drive the selection of a large fraction of macrophage-specific enhancers. Stimulus-regulated transcription factors primarily bind to DNA and activate gene expression at primed promoters and enhancers that contain their DNA recognition motifs and result in in recruitment of co-activator complexes that deposit H3K27ac. Binding of a stimulus regulated transcription factor to a promoter that is primed in many cell types is likely to result in a broad signal-dependent response. Binding of a stimulus regulated transcription factor to a cell-specific enhancer is likely to result in a cell restricted response or cell-specific potentiation of a broad response. H3K27Ac: histone H3 acetylated at lysine 27. H3K4me1: histone H3 monomethylation at lysine 4. NFR; nucleosome free region. TSS; transcriptional start site. SRTF; stimulus responsive transcription factor. GTF; general transcription factor (e.g., SP-1). LDTF; lineage determining TF (e.g. PU.1), SRTF; Stimulus responsive transcription factor, e.g., NFκB. H2a, H2b, H3, H4; histones H2a, 2b, 3 and 4, respectively.

Figure 4

Effect of natural genetic variation on enhancer selection and function. Two allelic forms of the genomic region shown at left are distinguished by a single nucleotide polymorphism (SNP) in the DNA recognition motif for PU.1. Genetic variant 1 (at top) preserves the PU.1 recognition motif, enabling PU.1 to bind and collaborate with other LDTFs and provide access to SRTFs. Genetic variant 2 disrupts the PU.1 motif, preventing PU.1 from binding and resulting in corresponding loss of binding of collaborative LDTFs and SRTFs. Because this genomic region only achieves features of active enhancers in cells that express the correct combinations of LDTFs and active SRTFs, effects of this SNP on gene expression are specific for those cell types, e.g., macrophages.