Zinc-dependent histone deacetylases drive neutrophil extracellular trap formation and potentiate local and systemic inflammation
| Autor: | Victor Pui-Yan Ma, Stephen J. Haggarty, Achille Broggi, Mehdi Benamar, Qian Chen, Ivan Zanoni, Valentina Poli, Marco Di Gioia, Ralph Mazitschek, Jeffrey M. Karp, Talal A. Chatila |
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| Přispěvatelé: | DUMENIL, Anita, Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, Brigham & Women’s Hospital [Boston] (BWH), Harvard Medical School [Boston] (HMS), Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Center for Systems Biology, Program in Membrane Biology and Division of Nephrology, Massachusetts General Hospital, Beth Israel Deaconess Medical Center [Boston] (BIDMC), Harvard Medical School [Boston] (HMS)-Harvard Medical School [Boston] (HMS), Harvard T.H. Chan School of Public Health, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA, Partenaires INRAE, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, Harvard-MIT Division of Health Sciences and Technology [Cambridge], Massachusetts Institute of Technology (MIT), Harvard Stem Cell Institute [Cambridge, USA] (HSCI), Harvard University [Cambridge], Harvard Medical School - Division of gastroenterology, Harvard University |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
ARDS
Cell biology Molecular biology Science [SDV]Life Sciences [q-bio] Immunology Inflammation Systemic inflammation Article Histone H3 medicine ComputingMilieux_MISCELLANEOUS Multidisciplinary biology Chemistry Neutrophil extracellular traps medicine.disease Chromatin [SDV] Life Sciences [q-bio] Histone citrullination Histone Functional aspects of cell biology biology.protein medicine.symptom |
| Zdroj: | iScience iScience, 2021, 24 (11), pp.103256. ⟨10.1016/j.isci.2021.103256⟩ iScience, Vol 24, Iss 11, Pp 103256-(2021) |
| ISSN: | 2589-0042 |
| Popis: | Summary Neutrophil 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 abstract Highlights • 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 inflammation Molecular biology; Immunology; Cell biology; Functional aspects of cell biology |
| Databáze: | OpenAIRE |
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