文章基本信息

标题：Zinc-dependent histone deacetylases drive neutrophil extracellular trap formation and potentiate local and systemic inflammation
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作者：Valentina Poli ; Victor Pui-Yan Ma ; Marco Di Gioia 等
期刊名称：iScience
印刷版ISSN：2589-0042
出版年度：2021
卷号：24
期号：11
页码：1-18
DOI：10.1016/j.isci.2021.103256
语种：English
出版社：Elsevier
摘要：SummaryNeutrophil extracellular traps (NETs) have been implicated in the pathogenesis of acute respiratory distress syndrome (ARDS) driven by viruses or bacteria, as well as in numerous immune-mediated disorders. Histone citrullination by the enzyme peptidylarginine deiminase 4 (PAD4) and the consequent decondensation of chromatin are hallmarks in the induction of NETs. Nevertheless, additional histone modifications that may govern NETosis are largely overlooked. Herein, we show that histone deacetylases (HDACs) play critical roles in driving NET formation in human and mouse neutrophils. HDACs belonging to the zinc-dependent lysine deacetylases family are necessary to deacetylate histone H3, thus allowing the activity of PAD4 and NETosis. Of note, HDAC inhibition in mice protects against microbial-induced pneumonia and septic shock, decreasing NETosis and inflammation. Collectively, our findings illustrate a new fundamental step that governs the release of NETs and points to HDAC inhibitors as therapeutic agents that may be used to protect against ARDS and sepsis.Graphical abstractDisplay OmittedHighlights•Zn-dependent lysine deacetylases govern neutrophil extracellular trap (NET) formation•Class I/IIb HDACs deacetylate histone H3 allowing its citrullination by PAD4•HDAC inhibition with ricolinostat protects against viral and bacterial pneumonia•In a model of endotoxic shock, ricolinostat inhibits NETosis and dampens inflammationMolecular biology; Immunology; Cell biology; Functional aspects of cell biology