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Immunity. 2019 Jun 18;50(6):1401-1411.e4. doi: 10.1016/j.immuni.2019.04.003. Epub 2019 May 7.

Inflammasome Activation Triggers Blood Clotting and Host Death through Pyroptosis.

Author information

1
Saha Cardiovascular Research Center, College of Medicine, University of Kentucky, Lexington, KY, USA.
2
Department of Chemistry, College of Arts and Sciences, University of Kentucky, Lexington, KY, USA.
3
National Institute of Biological Sciences, Beijing, China.
4
Division of Hematology and Oncology, Department of Medicine, McAllister Heart Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
5
Department of Hematology, Shanghai Tenth People's Hospital, Tongji University Cancer Center, Tongji University School of Medicine, Shanghai, China.
6
Department of Physiology, College of Medicine, University of Kentucky, Lexington, KY, USA.
7
Saha Cardiovascular Research Center, College of Medicine, University of Kentucky, Lexington, KY, USA; Department of Physiology, College of Medicine, University of Kentucky, Lexington, KY, USA.
8
Saha Cardiovascular Research Center, College of Medicine, University of Kentucky, Lexington, KY, USA; Veterans Affairs Medical Center, Lexington, KY, USA.
9
Department of Early Discovery Biochemistry, Genentech, Inc., South San Francisco, CA, USA.
10
Mammalian Genetics Laboratory, Genetic Strains Research Center, National Institute of Genetics, Mishima, Shizuoka, Japan.
11
Department of Chemistry, College of Arts and Sciences, University of Kentucky, Lexington, KY, USA. Electronic address: yinan.wei@uky.edu.
12
Saha Cardiovascular Research Center, College of Medicine, University of Kentucky, Lexington, KY, USA. Electronic address: zhenyuli08@uky.edu.

Abstract

Inflammasome activation and subsequent pyroptosis are critical defense mechanisms against microbes. However, overactivation of inflammasome leads to death of the host. Although recent studies have uncovered the mechanism of pyroptosis following inflammasome activation, how pyroptotic cell death drives pathogenesis, eventually leading to death of the host, is unknown. Here, we identified inflammasome activation as a trigger for blood clotting through pyroptosis. We have shown that canonical inflammasome activation by the conserved type III secretion system (T3SS) rod proteins from Gram-negative bacteria or noncanonical inflammasome activation by lipopolysaccharide (LPS) induced systemic blood clotting and massive thrombosis in tissues. Following inflammasome activation, pyroptotic macrophages released tissue factor (TF), an essential initiator of coagulation cascades. Genetic or pharmacological inhibition of TF abolishes inflammasome-mediated blood clotting and protects against death. Our data reveal that blood clotting is the major cause of host death following inflammasome activation and demonstrate that inflammasome bridges inflammation with thrombosis.

KEYWORDS:

DIC; GSDMD; LPS; caspase; coagulation; inflammasome; macrophage; pyroptosis; sepsis; tissue factor

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