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Journal Articles Nature Year : 2019

Externalized histone H4 orchestrates chronic inflammation by inducing lytic cell death

Carlos Silvestre-Roig
  • Function : Author
Quinte Braster
  • Function : Author
Nihel Berrebeh
Janine Winter
  • Function : Author
Patricia Lemnitzer
  • Function : Author
Almudena Ortega-Gómez
  • Function : Author
Raphaël Chèvre
  • Function : Author
Julia Marschner
  • Function : Author
Ariane Schumski
  • Function : Author
Carla Winter
  • Function : Author
Laura Perez-Olivares
  • Function : Author
Chang Pan
  • Function : Author
Nicole Paulin
  • Function : Author
Tom Schoufour
  • Function : Author
Helene Hartwig
  • Function : Author
Silvia González-Ramos
  • Function : Author
Frits Kamp
  • Function : Author
Remco Megens
  • Function : Author
Mat Gunzer
  • Function : Author
Tilman Hackeng
  • Function : Author
Esther Lutgens
  • Function : Author
Mat Daemen
  • Function : Author
Hans-Joachim Anders
  • Function : Author
Jean-Luc Pellequer
Christian Weber
  • Function : Author
Andrés Hidalgo
  • Function : Author
Oliver Soehnlein
  • Function : Author

Abstract

The perpetuation of inflammation is an important pathophysiological contributor to the global medical burden. Chronic inflammation is promoted by non-programmed cell death; 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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Dates and versions

hal-02128478 , version 1 (07-05-2021)

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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, 2019, 569 (7755), pp.236-240. ⟨10.1038/s41586-019-1167-6⟩. ⟨hal-02128478⟩
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