Tight 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
byPGE2. 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 factormyocyte
enhancer factor2A(MEF2A). Deletion ofMEF2AphenocopiedPGE2 treatmentand abolished type I
interferon (IFN I) induction upon exposure to innate immune stimuli. Mechanistically,PGE2 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. 

2021, Immunity 54, 1665–1682