TY - JOUR
T1 - Bacterial Endotoxin Activates the Coagulation Cascade through Gasdermin D-Dependent Phosphatidylserine Exposure
AU - Yang, Xinyu
AU - Cheng, Xiaoye
AU - Tang, Yiting
AU - Qiu, Xianhui
AU - Wang, Yupeng
AU - Kang, Haixia
AU - Wu, Jianfeng
AU - Wang, Zhongtai
AU - Liu, Yukun
AU - Chen, Fangping
AU - Xiao, Xianzhong
AU - Mackman, Nigel
AU - Billiar, Timothy R.
AU - Han, Jiahuai
AU - Lu, Ben
N1 - Funding Information:
We thank Xiangyu Wang for her excellent technical support. We thank Qianqian Xue for managing mouse colonies and research assistance. We thank Professor Feng Shao for providing key cell lines. We thank Professor Dongsheng Cao for the principal component analysis. This study was supported by the National key scientific project 2015CB910700 (to B.L.), National Natural Science Foundation of China ( 81930059 and 81470345 to B.L. and 81971893 to Y.T.), and Innovation-driven scientific project of CSU (to B.L.).
Funding Information:
We thank Xiangyu Wang for her excellent technical support. We thank Qianqian Xue for managing mouse colonies and research assistance. We thank Professor Feng Shao for providing key cell lines. We thank Professor Dongsheng Cao for the principal component analysis. This study was supported by the National key scientific project 2015CB910700 (to B.L.), National Natural Science Foundation of China (81930059 and 81470345 to B.L. and 81971893 to Y.T.), and Innovation-driven scientific project of CSU (to B.L.). B.L. conceived the project, designed the experiments, and wrote the manuscript. X.Y. X.C. Y.L. X.Q. Z.W. Y.W. H.K. and J.W. did the experiments. T.R.B. J.H. Y.T. F.C. and X.X. commented and edited the manuscript. J.H. and N.M. provided key reagents and transgenic mice. X.Y. and X.C. analyzed the data and made the figures. The authors declare no competing interests.
Publisher Copyright:
© 2019 Elsevier Inc.
PY - 2019/12/17
Y1 - 2019/12/17
N2 - Excessive activation of the coagulation system leads to life-threatening disseminated intravascular coagulation (DIC). Here, we examined the mechanisms underlying the activation of coagulation by lipopolysaccharide (LPS), the major cell-wall component of Gram-negative bacteria. We found that caspase-11, a cytosolic LPS receptor, activated the coagulation cascade. Caspase-11 enhanced the activation of tissue factor (TF), an initiator of coagulation, through triggering the formation of gasdermin D (GSDMD) pores and subsequent phosphatidylserine exposure, in a manner independent of cell death. GSDMD pores mediated calcium influx, which induced phosphatidylserine exposure through transmembrane protein 16F, a calcium-dependent phospholipid scramblase. Deletion of Casp11, ablation of Gsdmd, or neutralization of phosphatidylserine or TF prevented LPS-induced DIC. In septic patients, plasma concentrations of interleukin (IL)-1α and IL-1β, biomarkers of GSDMD activation, correlated with phosphatidylserine exposure in peripheral leukocytes and DIC scores. Our findings mechanistically link immune recognition of LPS to coagulation, with implications for the treatment of DIC.
AB - Excessive activation of the coagulation system leads to life-threatening disseminated intravascular coagulation (DIC). Here, we examined the mechanisms underlying the activation of coagulation by lipopolysaccharide (LPS), the major cell-wall component of Gram-negative bacteria. We found that caspase-11, a cytosolic LPS receptor, activated the coagulation cascade. Caspase-11 enhanced the activation of tissue factor (TF), an initiator of coagulation, through triggering the formation of gasdermin D (GSDMD) pores and subsequent phosphatidylserine exposure, in a manner independent of cell death. GSDMD pores mediated calcium influx, which induced phosphatidylserine exposure through transmembrane protein 16F, a calcium-dependent phospholipid scramblase. Deletion of Casp11, ablation of Gsdmd, or neutralization of phosphatidylserine or TF prevented LPS-induced DIC. In septic patients, plasma concentrations of interleukin (IL)-1α and IL-1β, biomarkers of GSDMD activation, correlated with phosphatidylserine exposure in peripheral leukocytes and DIC scores. Our findings mechanistically link immune recognition of LPS to coagulation, with implications for the treatment of DIC.
KW - caspase-11
KW - coagulation
KW - non-canonical inflammasome
KW - phosphatidylserine exposure
KW - sepsis
UR - http://www.scopus.com/inward/record.url?scp=85076128635&partnerID=8YFLogxK
U2 - 10.1016/j.immuni.2019.11.005
DO - 10.1016/j.immuni.2019.11.005
M3 - Article
C2 - 31836429
AN - SCOPUS:85076128635
SN - 1074-7613
VL - 51
SP - 983-996.e6
JO - Immunity
JF - Immunity
IS - 6
ER -