Abstract
SummaryTight control of inflammatory gene expression by antagonistic environmental cues is key to ensure immune protection while preventing tissue damage. Prostaglandin E2 (PGE2) modulates macrophage activation during homeostasis and disease, but the underlying mechanisms remain incompletely characterized. Here we dissected the genomic properties of lipopolysaccharide (LPS)-induced genes whose expression is antagonized by PGE2. The latter molecule targeted a set of inflammatory gene enhancers that, already in unstimulated macrophages, displayed poorly permissive chromatin organization and were marked by the transcription factor myocyte enhancer factor 2A (MEF2A). Deletion of MEF2A phenocopied PGE2 treatment and abolished type I interferon (IFN I) induction upon exposure to innate immune stimuli. Mechanistically, PGE2 interfered with LPS-mediated activation of ERK5, a known transcriptional partner of MEF2. This study highlights principles of plasticity and adaptation in cells exposed to a complex environment and uncovers a transcriptional circuit for IFN I induction with relevance for infectious diseases or cancer.
Highlights
Dynamic changes in gene expression enable biological processes during development and homeostasis and in response to stress
Prostaglandin E2 (PGE2), IL-10, and IL-4 target distinct sets of LPSinducible genes To characterize the effect of immune-modulatory signals on inflammatory gene expression, we performed RNA sequencing (RNA-seq) of mouse bone marrow-derived macrophages (BMDMs) left untreated (UT); stimulated for 4 h with lipopolysaccharide (LPS), PGE2, IL-10, or IL-4; or costimulated with LPS+PGE2, LPS+IL-10, or LPS+IL-4
We first defined LPSinducible genes (STAR Methods) and classified them as ‘‘PGE2-sensitive’’ (n = 70), ‘‘IL-10-sensitive’’ (n = 72), or ‘‘IL-4-sensitive’’ (n = 42) when their expression was lower in costimulated versus LPS-treated BMDMs
Summary
Dynamic changes in gene expression enable biological processes during development and homeostasis and in response to stress. Upon exposure to pathogenic insults, macrophages coordinately express hundreds of genes encoding for antimicrobial effectors, inflammatory cytokines, as well as positive and negative feedback regulators (Bhatt et al, 2012; Xue et al, 2014). This occurrence reflects locus-specific chromatin remodeling at promoters and enhancers, driven by combinations of lineage-determining and stimulus-activated transcription factors (TFs) (Garber et al, 2012; Ghisletti et al, 2010; Heinz et al, 2010; Kaikkonen et al, 2013; Ostuni et al, 2013). Inflammatory gene expression is controlled by immune-modulatory signals that co-exist in the same local milieu (Natoli and Ostuni, 2019)
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