Zinc-dependent histone deacetylases drive neutrophil extracellular trap formation and potentiate local and systemic inflammation

Valentina Poli; Victor Pui-Yan Ma; Marco Di Gioia; Achille Broggi; Mehdi Benamar; Qian Chen; Ralph Mazitschek; Stephen J. Haggarty; Talal A. Chatila; Jeffrey M. Karp; Ivan Zanoni

iScience (Nov 2021)

Zinc-dependent histone deacetylases drive neutrophil extracellular trap formation and potentiate local and systemic inflammation

Valentina Poli,
Victor Pui-Yan Ma,
Marco Di Gioia,
Achille Broggi,
Mehdi Benamar,
Qian Chen,
Ralph Mazitschek,
Stephen J. Haggarty,
Talal A. Chatila,
Jeffrey M. Karp,
Ivan Zanoni

Affiliations

Valentina Poli: Harvard Medical School, Boston Children's Hospital, Division of Immunology, Boston, 02115 MA, USA
Victor Pui-Yan Ma: Center for Nanomedicine, Department Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Harvard-MIT Division of Health Sciences and Technology, Boston, 02115 MA, USA
Marco Di Gioia: Harvard Medical School, Boston Children's Hospital, Division of Immunology, Boston, 02115 MA, USA
Achille Broggi: Harvard Medical School, Boston Children's Hospital, Division of Immunology, Boston, 02115 MA, USA
Mehdi Benamar: Harvard Medical School, Boston Children's Hospital, Division of Immunology, Boston, 02115 MA, USA
Qian Chen: Harvard Medical School, Boston Children's Hospital, Division of Immunology, Boston, 02115 MA, USA
Ralph Mazitschek: Center for Systems Biology, Massachusetts General Hospital, Boston, 02114 MA, USA; Harvard T.H. Chan School of Public Health, Boston, 02115 MA, USA; Broad Institute of MIT and Harvard, Cambridge, 02142 MA, USA
Stephen J. Haggarty: Chemical Neurobiology Laboratory, Center for Genomic Medicine, Departments of Neurology and Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, 02114 MA, USA
Talal A. Chatila: Harvard Medical School, Boston Children's Hospital, Division of Immunology, Boston, 02115 MA, USA
Jeffrey M. Karp: Center for Nanomedicine, Department Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Harvard-MIT Division of Health Sciences and Technology, Boston, 02115 MA, USA; Broad Institute of MIT and Harvard, Cambridge, 02142 MA, USA; Harvard-MIT Division of Health Sciences and Technology, Cambridge, 02139 MA, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, 02138 MA, USA; Corresponding author
Ivan Zanoni: Harvard Medical School, Boston Children's Hospital, Division of Immunology, Boston, 02115 MA, USA; Harvard Medical School, Boston Children's Hospital, Division of Gastroenterology, Boston, 02115 MA, USA; Corresponding author

Journal volume & issue: Vol. 24, no. 11
p. 103256

Abstract

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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.

Published in iScience

ISSN: 2589-0042 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Science
Website: http://www.cell.com/iscience/home

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