Externalized histone H4 orchestrates chronic inflammation by inducing lytic cell death

Carlos Silvestre-Roig*, Quinte Braster, Kanin Wichapong, Ernest Y. Lee, Jean Marie Teulon, Nihel Berrebeh, Janine Winter, Jose M. Adrover, Giancarlo Santiago Santos, Alexander Froese, Patricia Lemnitzer, Almudena Ortega-Gomez, Raphael Chevre, Julian Marschner, Ariane Schumski, Carla Winter, Laura Perez-Olivares, Chang Pan, Nicole Paulin, Tom SchoufourHelene Hartwig, Silvia Gonzalez-Ramos, Frits Kamp, Remco T. A. Megens, Kerri A. Mowen, Matthias Gunzer, Lars Maegdefessel, Tilman Hackeng, Esther Lutgens, Mat Daemen, Julia von Blume, Hans-Joachim Anders, Viacheslav O. Nikolaev, Jean-Luc Pellequer, Christian Weber, Andres Hidalgo, Gerry A. F. Nicolaes, Gerard C. L. Wong, Oliver Soehnlein*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

The perpetuation of inflammation is an important pathophysiological contributor to the global medical burden. Chronic inflammation is promoted by non-programmed cell death(1,)(2); however, how inflammation is instigated, its cellular and molecular mediators, and its therapeutic value are poorly defined. Here we use mouse models of atherosclerosis-a major underlying cause of mortality worldwide-to demonstrate that extracellular histone H4-mediated membrane lysis of smooth muscle cells (SMCs) triggers arterial tissue damage and inflammation. We show that activated lesional SMCs attract neutrophils, triggering the ejection of neutrophil extracellular traps that contain nuclear proteins. Among them, histone H4 binds to and lyses SMCs, leading to the destabilization of plaques; conversely, the neutralization of histone H4 prevents cell death of SMCs and stabilizes atherosclerotic lesions. Our data identify a form of cell death found at the core of chronic vascular disease that is instigated by leukocytes and can be targeted therapeutically.

Original languageEnglish
Pages (from-to)236-240
Number of pages25
JournalNature
Volume569
Issue number7755
DOIs
Publication statusPublished - 9 May 2019

Keywords

  • SMOOTH-MUSCLE-CELLS
  • EXTRACELLULAR HISTONES

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