意大利Vita-Salute 圣拉斐尔大学Renato Ostuni研究组取得一项新成果。他们研究发现前列腺素 E2 (PGE2)- 肌细胞增强因子 2A (MEF2A)轴使炎症基因表达的环境依赖控制成为可能。2021年6月14日出版的《免疫》杂志发表了这项成果。

他们剖析了脂多糖 (LPS) 诱导基因的基因组特性，其表达被 PGE2 拮抗。后一种分子靶向一组炎症基因增强子，这些基因增强子已经在未受刺激的巨噬细胞中显示出较差的染色质组织，并以转录因子MEF2A为标志。敲除MEF2A 的表型类似于施加PGE2并消除接触先天免疫刺激后的 I 型干扰素 (IFN I) 诱导。

从机制上讲，PGE2 干扰 LPS 介导的 ERK5 激活，ERK5 是 MEF2 的已知转录伙伴。这项研究强调了接触复杂环境的细胞的可塑性和适应原理，并揭示了与传染病或癌症相关的 IFN I 诱导的转录回路。

据悉，通过拮抗性环境因素严格控制炎症基因表达是确保免疫保护同时防止组织损伤的关键。PGE2 在体内平衡和疾病期间调节巨噬细胞活化，但其潜在机制仍未完全表征。

附：英文原文

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

Author: Francesco Cilenti, Giulia Barbiera, Nicoletta Caronni, Dario Iodice, Elisa Montaldo, Simona Barresi, Eleonora Lusito, Vincenzo Cuzzola, Francesco Maria Vittoria, Luca Mezzanzanica, Paolo Miotto, Pietro Di Lucia, Dejan Lazarevic, Daniela Maria Cirillo, Matteo Iannacone, Marco Genua, Renato Ostuni

Issue&Volume: 2021-06-14

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.

DOI: 10.1016/j.immuni.2021.05.016

Source: https://www.cell.com/immunity/fulltext/S1074-7613(21)00222-3