A PGE2-MEF2A axis enables context-dependent control of inflammatory gene expression

Abstract

Tight control of inflammatory gene expression by antagonistic environmental cues is key to ensure immune protection while preventing tissue damage. Prostaglandin E 2 (PGE 2 ) 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 PGE 2 . 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 PGE 2 treatment and abolished type I interferon (IFN I) induction upon exposure to innate immune stimuli. Mechanistically, PGE 2 interfered with LPSmediated 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.

4-Octyl-Itaconate and Dimethyl Fumarate Inhibit COX2 Expression and Prostaglandin Production in Macrophages

“…Therefore inhibition of PGE 2 by 4-OI could potentially be a factor in the downregulation of IL-6. Treatment of macrophages with PGE 2 was shown to boost production of IL-10 in macrophages ( 59 ), an anti-inflammatory cytokine that is also downregulated by 4-OI. It is also conceivable that a reduction in PGs secreted by macrophages could contribute to the anti-inflammatory effects of 4-OI during in vivo models ( 24 , 25 , 27 ).…”

External signals regulate continuous transcriptional states in hematopoietic stem cells

“…We performed over-representation analysis comparing various gene sets of interest (upregulated by stimulants, enriched in clusters) to a reference gene set. Depending on the analysis, the reference gene set was composed of an entire database of pathways (REACTOME, GO:BP), manually curated pathways of interest (searching for keywords on MSigDB database and from relevant publications; Goessling et al, 2011 ; Schuettpelz et al, 2014 ; Pedersen et al, 2016 ; Giladi et al, 2018 ; Mervosh et al, 2018 ; Patterson et al, 2020 ; Cilenti et al, 2021 ; Rodriguez-Fraticelli et al, 2020 ; Cabezas-Wallscheid et al, 2017 ) or gene sets generated from the analysis itself (marker genes from other clusters). Enrichment was assessed using a hypergeometric test (one-sided Fisher’s exact test) and p-values were corrected for FDR using Benjamini–Hochberg.…”

Macrophages, Metabolites, and Nucleosomes: Chromatin at the Intersection between Aging and Inflammation

“…As both gene sets responded to the same signal from the same receptor (TLR4) in different ways, the authors determined that in the initial round of transcription following LPS stimulation, unknown transcripts were generated that would suppress pro-inflammatory transcripts in tolerant macrophages. A more recent study showed epigenetic control over the modulation of cytokine production by the prostaglandin E2 (PGE 2 ) in human and murine macrophages [ 55 ]. Like other prostaglandins, PGE 2 is a lipid compound that is generated from arachidonic acid (AA), which is cleaved from membrane phospholipids by phospholipase A2 (PLA 2 ) enzymes.…”

“… Prostaglandin E 2 has context-dependent effects on inflammatory response in macrophages. (Left) Modulation of inflammation in human- and mouse-derived macrophages by Prostaglandin E 2 (PGE 2 ) stimulates increased cyclic adenosine monophosphate (cAMP) accumulation [ 55 ]. The transcription factor Myocyte Enhancer Factor 2A (MEF2a) activates the transcription of many lipopolysaccharide (LPS)-inducible genes in macrophages, including pro-inflammatory genes.…”

“…Therefore, PGE2 modulated macrophage response to LPS by suppressing the transcription of proinflammatory cytokines (Figure 3, left). [55]. The transcription factor Myocyte Enhancer Factor 2A (MEF2a) activates the transcription of many lipopolysaccharide (LPS)-inducible genes in macrophages, including pro-inflammatory genes.…”