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Externalized histone H4 orchestrates chronic inflammation by inducing lytic cell death

Carlos Silvestre-Roig 1 Quinte Braster 1 Kanin Wichapong 2 Ernest Lee 3 Jean-Marie Teulon 4 Nihel Berrebeh 4 Janine Winter 1 José Adrover 5 Giancarlo Santiago Santos 3 Alexander Froese 6 Patricia Lemnitzer 1 Almudena Ortega-Gómez 1 Raphaël Chèvre 1 Julia Marschner 7 Ariane Schumski 1 Carla Winter 1 Laura Perez-Olivares 1 Chang Pan 1 Nicole Paulin 1 Tom Schoufour 8 Helene Hartwig 1 Silvia González-Ramos 1 Frits Kamp 9 Remco Megens 1 Kerri Mowen 10 Mat Gunzer 11 Lars Maegdefessel 12 Tilman Hackeng 13 Esther Lutgens 1 Mat Daemen 14 Julia von Blume 15 Hans-Joachim Anders 16 Viacheslav Nikolaev 6 Jean-Luc Pellequer 4 Christian Weber 1 Andrés Hidalgo 1 Gerry Nicolaes 6 Gerard Wong 3 Oliver Soehnlein 1
Abstract : 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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Submitted on : Tuesday, May 14, 2019 - 12:03:36 PM
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Carlos Silvestre-Roig, Quinte Braster, Kanin Wichapong, Ernest Lee, Jean-Marie Teulon, et al.. Externalized histone H4 orchestrates chronic inflammation by inducing lytic cell death. Nature, Nature Publishing Group, 2019, 569 (7755), pp.236-240. ⟨10.1038/s41586-019-1167-6⟩. ⟨hal-02128478⟩



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