Extracellular Histones Trigger Disseminated Intravascular Coagulation by Lytic Cell Death

被引:12
|
作者
Zhang, Yan [1 ,2 ,3 ]
Wu, Congqing [2 ,4 ]
Li, Lan [5 ]
Pandeya, Ankit [5 ]
Zhang, Guoying [2 ,3 ]
Cui, Jian [5 ]
Kirchhofer, Daniel [6 ]
Wood, Jeremy P. [2 ]
Smyth, Susan S. [7 ]
Wei, Yinan [3 ,5 ]
Li, Zhenyu [2 ,3 ]
机构
[1] Soochow Univ, Dept Oncol, Affiliated Hosp 1, Suzhou 215006, Peoples R China
[2] Univ Kentucky, Coll Med, Saha Cardiovasc Res Ctr, Lexington, KY 40506 USA
[3] Texas A&M Univ, Irma Lerma Rangel Coll Pharm, Dept Pharmaceut Sci, College Stn, TX 76549 USA
[4] Univ Kentucky, Coll Med, Dept Surg, Lexington, KY 40506 USA
[5] Univ Kentucky, Coll Arts & Sci, Dept Chem, Lexington, KY 40506 USA
[6] Genentech Inc, Dept Early Discovery Biochem, San Francisco, CA 94080 USA
[7] Univ Arkansas Med Sci, Internal Med, Little Rock, AR 72205 USA
关键词
platelet; thrombocytopenia; histones; DIC; tissue factor; coagulation; cell death; THROMBIN GENERATION; INFLAMMATION; DNA; ACTIVATION; MEDIATORS; PROTECT; TLR2;
D O I
10.3390/ijms23126800
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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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页数:9
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