TY - JOUR
T1 - Externalized histone H4 orchestrates chronic inflammation by inducing lytic cell death
AU - Silvestre-Roig, Carlos
AU - Braster, Quinte
AU - Wichapong, Kanin
AU - Lee, Ernest Y.
AU - Teulon, Jean Marie
AU - Berrebeh, Nihel
AU - Winter, Janine
AU - Adrover, José M.
AU - Santos, Giancarlo Santiago
AU - Froese, Alexander
AU - Lemnitzer, Patricia
AU - Ortega-Gómez, Almudena
AU - Chevre, Raphael
AU - Marschner, Julian
AU - Schumski, Ariane
AU - Winter, Carla
AU - Perez-Olivares, Laura
AU - Pan, Chang
AU - Paulin, Nicole
AU - Schoufour, Tom
AU - Hartwig, Helene
AU - González-Ramos, Silvia
AU - Kamp, Frits
AU - Megens, Remco T.A.
AU - Mowen, Kerri A.
AU - Gunzer, Matthias
AU - Maegdefessel, Lars
AU - Hackeng, Tilman
AU - Lutgens, Esther
AU - Daemen, Mat
AU - von Blume, Julia
AU - Anders, Hans Joachim
AU - Nikolaev, Viacheslav O.
AU - Pellequer, Jean Luc
AU - Weber, Christian
AU - Hidalgo, Andrés
AU - Nicolaes, Gerry A.F.
AU - Wong, Gerard C.L.
AU - Soehnlein, Oliver
N1 - Publisher Copyright:
© 2019, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2019/5/9
Y1 - 2019/5/9
N2 - 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.
AB - 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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U2 - 10.1038/s41586-019-1167-6
DO - 10.1038/s41586-019-1167-6
M3 - Article
C2 - 31043745
AN - SCOPUS:85065241178
SN - 0028-0836
VL - 569
SP - 236
EP - 240
JO - Nature
JF - Nature
IS - 7755
ER -