Inflammasome Activation Triggers Blood Clotting and Host Death through Pyroptosis

Congqing Wu; Wei Lu; Yan Zhang; Guoying Zhang; Xuyan Shi; Yohei Hisada; Steven P. Grover; Xinyi Zhang; Lan Li; Binggang Xiang; Jumei Shi; Xiang An Li; Alan Daugherty; Susan S. Smyth; Daniel Kirchhofer; Toshihiko Shiroishi; Feng Shao; Nigel Mackman; Yinan Wei; Zhenyu Li

doi:10.1016/j.immuni.2019.04.003

Inflammasome Activation Triggers Blood Clotting and Host Death through Pyroptosis

Congqing Wu, Wei Lu, Yan Zhang, Guoying Zhang, Xuyan Shi, Yohei Hisada, Steven P. Grover, Xinyi Zhang, Lan Li, Binggang Xiang, Jumei Shi, Xiang An Li, Alan Daugherty, Susan S. Smyth, Daniel Kirchhofer, Toshihiko Shiroishi, Feng Shao, Nigel Mackman, Yinan Wei, Zhenyu Li

Research output: Contribution to journal › Article › peer-review

166 Citations (SciVal)

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. Overactivation of inflammasome leads to death of the host. Wu and colleagues demonstrate that activation of coagulation is responsible for inflammasome activation-induced death.

Original language	English
Pages (from-to)	1401-1411.e4
Journal	Immunity
Volume	50
Issue number	6
DOIs	https://doi.org/10.1016/j.immuni.2019.04.003
State	Published - Jun 18 2019

Bibliographical note

Funding Information:
C.W. is supported by AHA Great Rivers Affiliate Postdoctoral Fellowship 16POST31140008 and is a K99 awardee ( K99HL145117 ; NHLBI ). J.S. is supported by National Natural Science Foundation of China 81372391 . X.L. is supported by NIH R01 GM121796 . Y.W. is supported by AHA Great Rivers Affiliate Grant-in-Aid 17GRNT33410327 , NSF CHE-1709381 , NIH / NIAID R56 AI137020 and R21 AI142063 , and NIH / NHLBI R01 HL142640 . Z.L. is supported by NIH / NHLBI R01 HL123927 and R01 HL142640 . Dr. Wendy Katz provided help with tissue paraffin embedding and sectioning and was supported by NIH / NIGMS Institutional Development Award P20GM103527 . Dr. Thomas Wilkop at UK Light Microscopy Core provided help with intravital microscopy. Dr. Wei Li at Marshall University provided help with isolation of mouse cremaster muscle. Dr. Hartmut Weiler at Medical College of Wisconsin and Dr. Rodney M. Camire at the University of Pennsylvania provided fibrin antibodies.

Funding Information:
C.W. is supported by AHA Great Rivers Affiliate Postdoctoral Fellowship 16POST31140008 and is a K99 awardee (K99HL145117; NHLBI). J.S. is supported by National Natural Science Foundation of China 81372391. X.L. is supported by NIH R01 GM121796. Y.W. is supported by AHA Great Rivers Affiliate Grant-in-Aid 17GRNT33410327, NSF CHE-1709381, NIH/NIAID R56 AI137020 and R21 AI142063, and NIH/NHLBI R01 HL142640. Z.L. is supported by NIH/NHLBI R01 HL123927 and R01 HL142640. Dr. Wendy Katz provided help with tissue paraffin embedding and sectioning and was supported by NIH/NIGMS Institutional Development Award P20GM103527. Dr. Thomas Wilkop at UK Light Microscopy Core provided help with intravital microscopy. Dr. Wei Li at Marshall University provided help with isolation of mouse cremaster muscle. Dr. Hartmut Weiler at Medical College of Wisconsin and Dr. Rodney M. Camire at the University of Pennsylvania provided fibrin antibodies. C.W. Y.W. and Z.L. designed and performed the experiments and wrote the manuscript, assisted by W.L. Y.Z. G.Z. X.S. Y.H. S.P.G. X.Z. L.L. B.X. and J.S. X.-A.L. A.D. S.S.S. N.M. and F.S. contributed to manuscript preparation. D.K. T.S. and N.M. provided mice and/or reagents and discussed experiments. All authors discussed the results and commented on the manuscript. D.K. is an employee of Genentech Inc.

Publisher Copyright:
© 2019 Elsevier Inc.

Keywords

DIC
GSDMD
LPS
caspase
coagulation
inflammasome
macrophage
pyroptosis
sepsis
tissue factor

ASJC Scopus subject areas

Immunology and Allergy
Immunology
Infectious Diseases

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.immuni.2019.04.003

Cite this

Wu, C., Lu, W., Zhang, Y., Zhang, G., Shi, X., Hisada, Y., Grover, S. P., Zhang, X., Li, L., Xiang, B., Shi, J., Li, X. A., Daugherty, A., Smyth, S. S., Kirchhofer, D., Shiroishi, T., Shao, F., Mackman, N., Wei, Y., & Li, Z. (2019). Inflammasome Activation Triggers Blood Clotting and Host Death through Pyroptosis. Immunity, 50(6), 1401-1411.e4. https://doi.org/10.1016/j.immuni.2019.04.003

@article{a44867cc962c496183acf36faa99ad53,

title = "Inflammasome Activation Triggers Blood Clotting and Host Death through Pyroptosis",

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. Overactivation of inflammasome leads to death of the host. Wu and colleagues demonstrate that activation of coagulation is responsible for inflammasome activation-induced death.",

keywords = "DIC, GSDMD, LPS, caspase, coagulation, inflammasome, macrophage, pyroptosis, sepsis, tissue factor",

author = "Congqing Wu and Wei Lu and Yan Zhang and Guoying Zhang and Xuyan Shi and Yohei Hisada and Grover, {Steven P.} and Xinyi Zhang and Lan Li and Binggang Xiang and Jumei Shi and Li, {Xiang An} and Alan Daugherty and Smyth, {Susan S.} and Daniel Kirchhofer and Toshihiko Shiroishi and Feng Shao and Nigel Mackman and Yinan Wei and Zhenyu Li",

note = "Funding Information: C.W. is supported by AHA Great Rivers Affiliate Postdoctoral Fellowship 16POST31140008 and is a K99 awardee ( K99HL145117 ; NHLBI ). J.S. is supported by National Natural Science Foundation of China 81372391 . X.L. is supported by NIH R01 GM121796 . Y.W. is supported by AHA Great Rivers Affiliate Grant-in-Aid 17GRNT33410327 , NSF CHE-1709381 , NIH / NIAID R56 AI137020 and R21 AI142063 , and NIH / NHLBI R01 HL142640 . Z.L. is supported by NIH / NHLBI R01 HL123927 and R01 HL142640 . Dr. Wendy Katz provided help with tissue paraffin embedding and sectioning and was supported by NIH / NIGMS Institutional Development Award P20GM103527 . Dr. Thomas Wilkop at UK Light Microscopy Core provided help with intravital microscopy. Dr. Wei Li at Marshall University provided help with isolation of mouse cremaster muscle. Dr. Hartmut Weiler at Medical College of Wisconsin and Dr. Rodney M. Camire at the University of Pennsylvania provided fibrin antibodies. Funding Information: C.W. is supported by AHA Great Rivers Affiliate Postdoctoral Fellowship 16POST31140008 and is a K99 awardee (K99HL145117; NHLBI). J.S. is supported by National Natural Science Foundation of China 81372391. X.L. is supported by NIH R01 GM121796. Y.W. is supported by AHA Great Rivers Affiliate Grant-in-Aid 17GRNT33410327, NSF CHE-1709381, NIH/NIAID R56 AI137020 and R21 AI142063, and NIH/NHLBI R01 HL142640. Z.L. is supported by NIH/NHLBI R01 HL123927 and R01 HL142640. Dr. Wendy Katz provided help with tissue paraffin embedding and sectioning and was supported by NIH/NIGMS Institutional Development Award P20GM103527. Dr. Thomas Wilkop at UK Light Microscopy Core provided help with intravital microscopy. Dr. Wei Li at Marshall University provided help with isolation of mouse cremaster muscle. Dr. Hartmut Weiler at Medical College of Wisconsin and Dr. Rodney M. Camire at the University of Pennsylvania provided fibrin antibodies. C.W. Y.W. and Z.L. designed and performed the experiments and wrote the manuscript, assisted by W.L. Y.Z. G.Z. X.S. Y.H. S.P.G. X.Z. L.L. B.X. and J.S. X.-A.L. A.D. S.S.S. N.M. and F.S. contributed to manuscript preparation. D.K. T.S. and N.M. provided mice and/or reagents and discussed experiments. All authors discussed the results and commented on the manuscript. D.K. is an employee of Genentech Inc. Publisher Copyright: {\textcopyright} 2019 Elsevier Inc.",

year = "2019",

month = jun,

day = "18",

doi = "10.1016/j.immuni.2019.04.003",

language = "English",

volume = "50",

pages = "1401--1411.e4",

number = "6",

}

Wu, C, Lu, W, Zhang, Y, Zhang, G, Shi, X, Hisada, Y, Grover, SP, Zhang, X, Li, L, Xiang, B, Shi, J, Li, XA , Daugherty, A, Smyth, SS, Kirchhofer, D, Shiroishi, T, Shao, F, Mackman, N, Wei, Y & Li, Z 2019, 'Inflammasome Activation Triggers Blood Clotting and Host Death through Pyroptosis', Immunity, vol. 50, no. 6, pp. 1401-1411.e4. https://doi.org/10.1016/j.immuni.2019.04.003

TY - JOUR

T1 - Inflammasome Activation Triggers Blood Clotting and Host Death through Pyroptosis

AU - Wu, Congqing

AU - Lu, Wei

AU - Zhang, Yan

AU - Zhang, Guoying

AU - Shi, Xuyan

AU - Hisada, Yohei

AU - Grover, Steven P.

AU - Zhang, Xinyi

AU - Li, Lan

AU - Xiang, Binggang

AU - Shi, Jumei

AU - Li, Xiang An

AU - Daugherty, Alan

AU - Smyth, Susan S.

AU - Kirchhofer, Daniel

AU - Shiroishi, Toshihiko

AU - Shao, Feng

AU - Mackman, Nigel

AU - Wei, Yinan

AU - Li, Zhenyu

N1 - Funding Information: C.W. is supported by AHA Great Rivers Affiliate Postdoctoral Fellowship 16POST31140008 and is a K99 awardee ( K99HL145117 ; NHLBI ). J.S. is supported by National Natural Science Foundation of China 81372391 . X.L. is supported by NIH R01 GM121796 . Y.W. is supported by AHA Great Rivers Affiliate Grant-in-Aid 17GRNT33410327 , NSF CHE-1709381 , NIH / NIAID R56 AI137020 and R21 AI142063 , and NIH / NHLBI R01 HL142640 . Z.L. is supported by NIH / NHLBI R01 HL123927 and R01 HL142640 . Dr. Wendy Katz provided help with tissue paraffin embedding and sectioning and was supported by NIH / NIGMS Institutional Development Award P20GM103527 . Dr. Thomas Wilkop at UK Light Microscopy Core provided help with intravital microscopy. Dr. Wei Li at Marshall University provided help with isolation of mouse cremaster muscle. Dr. Hartmut Weiler at Medical College of Wisconsin and Dr. Rodney M. Camire at the University of Pennsylvania provided fibrin antibodies. Funding Information: C.W. is supported by AHA Great Rivers Affiliate Postdoctoral Fellowship 16POST31140008 and is a K99 awardee (K99HL145117; NHLBI). J.S. is supported by National Natural Science Foundation of China 81372391. X.L. is supported by NIH R01 GM121796. Y.W. is supported by AHA Great Rivers Affiliate Grant-in-Aid 17GRNT33410327, NSF CHE-1709381, NIH/NIAID R56 AI137020 and R21 AI142063, and NIH/NHLBI R01 HL142640. Z.L. is supported by NIH/NHLBI R01 HL123927 and R01 HL142640. Dr. Wendy Katz provided help with tissue paraffin embedding and sectioning and was supported by NIH/NIGMS Institutional Development Award P20GM103527. Dr. Thomas Wilkop at UK Light Microscopy Core provided help with intravital microscopy. Dr. Wei Li at Marshall University provided help with isolation of mouse cremaster muscle. Dr. Hartmut Weiler at Medical College of Wisconsin and Dr. Rodney M. Camire at the University of Pennsylvania provided fibrin antibodies. C.W. Y.W. and Z.L. designed and performed the experiments and wrote the manuscript, assisted by W.L. Y.Z. G.Z. X.S. Y.H. S.P.G. X.Z. L.L. B.X. and J.S. X.-A.L. A.D. S.S.S. N.M. and F.S. contributed to manuscript preparation. D.K. T.S. and N.M. provided mice and/or reagents and discussed experiments. All authors discussed the results and commented on the manuscript. D.K. is an employee of Genentech Inc. Publisher Copyright: © 2019 Elsevier Inc.

PY - 2019/6/18

Y1 - 2019/6/18

N2 - 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. Overactivation of inflammasome leads to death of the host. Wu and colleagues demonstrate that activation of coagulation is responsible for inflammasome activation-induced death.

AB - 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. Overactivation of inflammasome leads to death of the host. Wu and colleagues demonstrate that activation of coagulation is responsible for inflammasome activation-induced death.

KW - DIC

KW - GSDMD

KW - LPS

KW - caspase

KW - coagulation

KW - inflammasome

KW - macrophage

KW - pyroptosis

KW - sepsis

KW - tissue factor

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Inflammasome Activation Triggers Blood Clotting and Host Death through Pyroptosis

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

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