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Extracellular Histones Trigger Disseminated Intravascular Coagulation by Lytic Cell Death

Histones are cationic nuclear proteins that are essential for the structure and functions of eukaryotic chromatin. However, extracellular histones trigger inflammatory responses and contribute to death in sepsis by unknown mechanisms. We recently reported that inflammasome activation and pyroptosis...

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Autores principales: Zhang, Yan, Wu, Congqing, Li, Lan, Pandeya, Ankit, Zhang, Guoying, Cui, Jian, Kirchhofer, Daniel, Wood, Jeremy P., Smyth, Susan S., Wei, Yinan, Li, Zhenyu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9224270/
https://www.ncbi.nlm.nih.gov/pubmed/35743244
http://dx.doi.org/10.3390/ijms23126800
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author Zhang, Yan
Wu, Congqing
Li, Lan
Pandeya, Ankit
Zhang, Guoying
Cui, Jian
Kirchhofer, Daniel
Wood, Jeremy P.
Smyth, Susan S.
Wei, Yinan
Li, Zhenyu
author_facet Zhang, Yan
Wu, Congqing
Li, Lan
Pandeya, Ankit
Zhang, Guoying
Cui, Jian
Kirchhofer, Daniel
Wood, Jeremy P.
Smyth, Susan S.
Wei, Yinan
Li, Zhenyu
author_sort Zhang, Yan
collection PubMed
description Histones are cationic nuclear proteins that are essential for the structure and functions of eukaryotic chromatin. However, extracellular histones trigger inflammatory responses and contribute to death in sepsis by unknown mechanisms. We recently reported that inflammasome activation and pyroptosis trigger coagulation activation through a tissue-factor (TF)-dependent mechanism. We used a combination of various deficient mice to elucidate the molecular mechanism of histone-induced coagulation. We showed that histones trigger coagulation activation in vivo, as evidenced by coagulation parameters and fibrin deposition in tissues. However, histone-induced coagulopathy was neither dependent on intracellular inflammasome pathways involving caspase 1/11 and gasdermin D (GSDMD), nor on cell surface receptor TLR2- and TLR4-mediated host immune response, as the deficiency of these genes in mice did not protect against histone-induced coagulopathy. The incubation of histones with macrophages induced lytic cell death and phosphatidylserine (PS) exposure, which is required for TF activity, a key initiator of coagulation. The neutralization of TF diminished the histone-induced coagulation. Our findings revealed lytic cell death as a novel mechanism of histone-induced coagulation activation and thrombosis.
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spelling pubmed-92242702022-06-24 Extracellular Histones Trigger Disseminated Intravascular Coagulation by Lytic Cell Death Zhang, Yan Wu, Congqing Li, Lan Pandeya, Ankit Zhang, Guoying Cui, Jian Kirchhofer, Daniel Wood, Jeremy P. Smyth, Susan S. Wei, Yinan Li, Zhenyu Int J Mol Sci Brief Report Histones are cationic nuclear proteins that are essential for the structure and functions of eukaryotic chromatin. However, extracellular histones trigger inflammatory responses and contribute to death in sepsis by unknown mechanisms. We recently reported that inflammasome activation and pyroptosis trigger coagulation activation through a tissue-factor (TF)-dependent mechanism. We used a combination of various deficient mice to elucidate the molecular mechanism of histone-induced coagulation. We showed that histones trigger coagulation activation in vivo, as evidenced by coagulation parameters and fibrin deposition in tissues. However, histone-induced coagulopathy was neither dependent on intracellular inflammasome pathways involving caspase 1/11 and gasdermin D (GSDMD), nor on cell surface receptor TLR2- and TLR4-mediated host immune response, as the deficiency of these genes in mice did not protect against histone-induced coagulopathy. The incubation of histones with macrophages induced lytic cell death and phosphatidylserine (PS) exposure, which is required for TF activity, a key initiator of coagulation. The neutralization of TF diminished the histone-induced coagulation. Our findings revealed lytic cell death as a novel mechanism of histone-induced coagulation activation and thrombosis. MDPI 2022-06-18 /pmc/articles/PMC9224270/ /pubmed/35743244 http://dx.doi.org/10.3390/ijms23126800 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Brief Report
Zhang, Yan
Wu, Congqing
Li, Lan
Pandeya, Ankit
Zhang, Guoying
Cui, Jian
Kirchhofer, Daniel
Wood, Jeremy P.
Smyth, Susan S.
Wei, Yinan
Li, Zhenyu
Extracellular Histones Trigger Disseminated Intravascular Coagulation by Lytic Cell Death
title Extracellular Histones Trigger Disseminated Intravascular Coagulation by Lytic Cell Death
title_full Extracellular Histones Trigger Disseminated Intravascular Coagulation by Lytic Cell Death
title_fullStr Extracellular Histones Trigger Disseminated Intravascular Coagulation by Lytic Cell Death
title_full_unstemmed Extracellular Histones Trigger Disseminated Intravascular Coagulation by Lytic Cell Death
title_short Extracellular Histones Trigger Disseminated Intravascular Coagulation by Lytic Cell Death
title_sort extracellular histones trigger disseminated intravascular coagulation by lytic cell death
topic Brief Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9224270/
https://www.ncbi.nlm.nih.gov/pubmed/35743244
http://dx.doi.org/10.3390/ijms23126800
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