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.
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.
Immunity. 2021 Aug 10;54(8):1665-1682.e14. doi: 10.1016/j.immuni.2021.05.016. Epub 2021 Jun 14.
Tight control of inflammatory gene expression by antagonistic environmental cues is key to ensure immune protection while preventing tissue damage. Prostaglandin E (PGE) 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. 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 treatment and abolished type I interferon (IFN I) induction upon exposure to innate immune stimuli. Mechanistically, PGE 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.
通过拮抗环境信号来严格控制炎症基因的表达，是确保免疫保护同时防止组织损伤的关键。前列腺素 E (PGE) 在稳态和疾病期间调节巨噬细胞的激活，但潜在的机制仍不完全清楚。在这里，我们解析了脂多糖 (LPS) 诱导的基因的基因组特性，这些基因的表达受到 PGE 的拮抗。后者靶向一组炎症基因增强子，在未受刺激的巨噬细胞中，这些增强子已经显示出较差的可及染色质组织，并被转录因子肌细胞增强因子 2A (MEF2A) 标记。删除 MEF2A 可模拟 PGE 处理，并在暴露于先天免疫刺激物时消除 I 型干扰素 (IFN I) 的诱导。从机制上讲，PGE 干扰了 LPS 介导的 ERK5 的激活，ERK5 是 MEF2 的已知转录伙伴。这项研究强调了暴露于复杂环境中的细胞的可塑性和适应性原则，并揭示了与传染病或癌症相关的 IFN I 诱导的转录回路。
