Externalized histone H4 orchestrates chronic inflammation by inducing lytic cell death

The perpetuation of inflammation is an important pathophysiological contributor to the global medical burden. Chronic inflammation is promoted by non-programmed cell death 1 , 2 ; however, how inflammation is instigated, its cellular and molecular mediators, and its therapeutic value are poorly defi...

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Published in:	Nature (London) Vol. 569; no. 7755; pp. 236 - 240
Main Authors:	Silvestre-Roig, Carlos, Braster, Quinte, Wichapong, Kanin, Lee, Ernest Y., Teulon, Jean Marie, Berrebeh, Nihel, Winter, Janine, Adrover, José M., Santos, Giancarlo Santiago, Froese, Alexander, Lemnitzer, Patricia, Ortega-Gómez, Almudena, Chevre, Raphael, Marschner, Julian, Schumski, Ariane, Winter, Carla, Perez-Olivares, Laura, Pan, Chang, Paulin, Nicole, Schoufour, Tom, Hartwig, Helene, González-Ramos, Silvia, Kamp, Frits, Megens, Remco T. A., Mowen, Kerri A., Gunzer, Matthias, Maegdefessel, Lars, Hackeng, Tilman, Lutgens, Esther, Daemen, Mat, von Blume, Julia, Anders, Hans-Joachim, Nikolaev, Viacheslav O., Pellequer, Jean-Luc, Weber, Christian, Hidalgo, Andrés, Nicolaes, Gerry A. F., Wong, Gerard C. L., Soehnlein, Oliver
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 01.05.2019 Nature Publishing Group
Subjects:	13/1 13/2 13/21 13/31 13/51 14 14/1 14/19 14/28 14/3 14/69 631/80/82 64/110 64/60 692/420/256/2515 692/699/75/593/2100 82/29 82/51 Animal models Animals Apoptosis Arteries - pathology Arteriosclerosis Artificial intelligence Atherosclerosis Atherosclerosis - pathology Biochemistry Cell adhesion & migration Cell Death Cell Membrane - drug effects Cell Membrane - metabolism Cellular Biology Chemokines Cytotoxicity Destabilization Disease Models, Animal Ejection Female Histone H4 Histones Histones - antagonists & inhibitors Histones - metabolism Humanities and Social Sciences Inflammation Inflammation - metabolism Inflammation - pathology Lesions Letter Leukocytes Leukocytes (neutrophilic) Life Sciences Lysis Mice Mice, Inbred C57BL Mortality multidisciplinary Muscles Myocytes, Smooth Muscle - pathology Neutralization Neutropenia Neutrophils Neutrophils - cytology Observations Open source software Peptides Physiological aspects Plaques Porosity Protein Binding - drug effects Proteins Science Science (multidisciplinary) Smooth muscle Vascular diseases Germany
ISSN:	0028-0836, 1476-4687, 1476-4687
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Summary:	The perpetuation of inflammation is an important pathophysiological contributor to the global medical burden. Chronic inflammation is promoted by non-programmed cell death 1 , 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. Histone H4 is released from neutrophil extracellular traps and induces membrane lysis in vascular smooth muscle cells, leading to the destabilization of atherosclerotic plaques.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 Author contributions C.S.-R. and Q.B. designed and performed experiments, analysed data, interpreted data and wrote the manuscript. K.W., E.Y.L., J.M.T., N.B., J.W., J.M.A., G.S.S., A.F., A.O.-G., J.M., P.L., R.C., A.S., C. Winter, L.P.-O., C.P., T.S., H.H., J.v.B. and S.G.-R. contributed to data acquisition and analysis; N.P. supervised animal experimentation; F.K., R.T.A.M., H.-J.A., V.O.N., A.H., J.-L.P., G.C.L.W. and G.A.F.N. supervised specific data acquisition and analysis and provided funding; C. Weber provided scientific infrastructure, access to Lyz2creCxcr4flox mice, and contributed to the funding of K.W.; K.A.M. provided Pad4 mice; M.G. provided Ly6gcre mice; T.H. synthetized peptides; and L.M., E.L. and M.D. provided human samples and contributed to data analyses. O.S. conceived and supervised the study, designed experiments and interpreted data, provided funding and wrote the paper. A.H., G.C.L.W. and G.A.F.N. contributed equally to this study.
ISSN:	0028-0836 1476-4687 1476-4687
DOI:	10.1038/s41586-019-1167-6