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Externalized histone H4 orchestrates chronic inflammation by inducing lytic cell death.


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.

SUBMITTER: Silvestre-Roig C 

PROVIDER: S-EPMC6716525 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Externalized histone H4 orchestrates chronic inflammation by inducing lytic cell death.

Silvestre-Roig Carlos C   Braster Quinte Q   Wichapong Kanin K   Lee Ernest Y EY   Teulon Jean Marie JM   Berrebeh Nihel N   Winter Janine J   Adrover José M JM   Santos Giancarlo Santiago GS   Froese Alexander A   Lemnitzer Patricia P   Ortega-Gómez Almudena A   Chevre Raphael R   Marschner Julian J   Schumski Ariane A   Winter Carla C   Perez-Olivares Laura L   Pan Chang C   Paulin Nicole N   Schoufour Tom T   Hartwig Helene H   González-Ramos Silvia S   Kamp Frits F   Megens Remco T A RTA   Mowen Kerri A KA   Gunzer Matthias M   Maegdefessel Lars L   Hackeng Tilman T   Lutgens Esther E   Daemen Mat M   von Blume Julia J   Anders Hans-Joachim HJ   Nikolaev Viacheslav O VO   Pellequer Jean-Luc JL   Weber Christian C   Hidalgo Andrés A   Nicolaes Gerry A F GAF   Wong Gerard C L GCL   Soehnlein Oliver O  

Nature 20190501 7755


The perpetuation of inflammation is an important pathophysiological contributor to the global medical burden. Chronic inflammation is promoted by non-programmed cell death<sup>1,2</sup>; 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 (SMC  ...[more]

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