A PGE 2-MEF2A axis enables context-dependent control of inflammatory gene expression

Immunity. 2021 Jun 9;S1074-7613(21)00222-3. doi: 10.1016/j.immuni.2021.05.016. | PubMed

Francesco Cilenti¹, Giulia Barbiera², Nicoletta Caronni², Dario Iodice², Elisa Montaldo², Simona Barresi², Eleonora Lusito², Vincenzo Cuzzola², Francesco Maria Vittoria¹, Luca Mezzanzanica¹, Paolo Miotto³, Pietro Di Lucia⁴, Dejan Lazarevic⁵, Daniela Maria Cirillo³, Matteo Iannacone⁶, Marco Genua², Renato Ostuni⁷

1. Vita-Salute San Raffaele University, Milan, Italy; San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), Milan, Italy; Genomics of the Innate Immune System Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.
2. San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), Milan, Italy; Genomics of the Innate Immune System Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.
3. Emerging Bacterial Pathogens Unit, Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy.
4. Dynamics of Immune Responses Unit, Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy.
5. Center for Omics Sciences (COSR), IRCCS San Raffaele Scientific Institute, Milan, Italy.
6. Vita-Salute San Raffaele University, Milan, Italy; Dynamics of Immune Responses Unit, Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy; Experimental Imaging Centre, IRCCS San Raffaele Scientific Institute, Milan, Italy.
7. Vita-Salute San Raffaele University, Milan, Italy; San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), Milan, Italy; Genomics of the Innate Immune System Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy. Electronic address: ostuni.renato@hsr.it.

Abstract

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 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.

Presented By Francesco Cilenti | ORCID iD