Ludwig-Maximilians-Universität, Chair of Metabolic Biochemistry

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Externalized histone H4 orchestrates chronic inflammation by inducing lytic cell death

Nature. 2019 May;569(7755):236-240

Authors/Editors: Carlos Silvestre-Roig
Quinte Braster
Kanin Wichapong
Ernest Y Lee
Jean Marie Teulon
Nihel Berrebeh
Janine Winter
José M Adrover
Giancarlo Santiago Santos
Alexander Froese
Patricia Lemnitzer
Almudena Ortega-Gómez
Raphael Chevre
Julian Marschner
Ariane Schumski
Carla Winter
Laura Perez-Olivares
Chang Pan
Nicole Paulin
Tom Schoufour
Helene Hartwig
Silvia González-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
Andrés Hidalgo
Gerry A F Nicolaes
Gerard C L Wong
Oliver Soehnlein
Publication Date: 2019
Type of Publication: Journal Article

The perpetuation of inflammation is an important pathophysiological contributor to the global medical burden. Chronic inflammation is promoted by non-programmed cell death1,2; 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.

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