Inhibition of caspase-1-mediated inflammasome activation reduced blood coagulation in cerebrospinal fluid after subarachnoid haemorrhage
Yuanjian Fang,
Xiaoyu Wang,
Jianan Lu,
Hui Shi,
Lei Huang,
Anwen Shao,
Anke Zhang,
Yibo Liu,
Reng Ren,
Cameron Lenahan,
Jiping Tang,
Jianmin Zhang,
John H. Zhang,
Sheng Chen
Affiliations
Yuanjian Fang
Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, 88 Jiefang Road, Hangzhou, Zhejiang 310009, China
Xiaoyu Wang
Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, 88 Jiefang Road, Hangzhou, Zhejiang 310009, China
Jianan Lu
Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, 88 Jiefang Road, Hangzhou, Zhejiang 310009, China
Hui Shi
Department of Neurosurgery, Yongchuan Hospital, Chongqing Medical University, Chongqing, China
Lei Huang
Department of Neurosurgery, Loma Linda University, 11041 Campus St, Risley Hall, Room 219, Loma Linda, CA 92354, United States; Department of Physiology and Pharmacology, Loma Linda University, Loma Linda, CA, United States
Anwen Shao
Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, 88 Jiefang Road, Hangzhou, Zhejiang 310009, China
Anke Zhang
Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, 88 Jiefang Road, Hangzhou, Zhejiang 310009, China
Yibo Liu
Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, 88 Jiefang Road, Hangzhou, Zhejiang 310009, China
Reng Ren
Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, 88 Jiefang Road, Hangzhou, Zhejiang 310009, China
Cameron Lenahan
Department of Neurosurgery, Loma Linda University, 11041 Campus St, Risley Hall, Room 219, Loma Linda, CA 92354, United States; Burrell College of Osteopathic Medicine, Las Cruces, NM, United States
Jiping Tang
Department of Neurosurgery, Loma Linda University, 11041 Campus St, Risley Hall, Room 219, Loma Linda, CA 92354, United States; Department of Physiology and Pharmacology, Loma Linda University, Loma Linda, CA, United States; Department of Anesthesiology, Loma Linda University, Loma Linda, CA, United States
Jianmin Zhang
Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, 88 Jiefang Road, Hangzhou, Zhejiang 310009, China; Corresponding authors.
John H. Zhang
Department of Neurosurgery, Loma Linda University, 11041 Campus St, Risley Hall, Room 219, Loma Linda, CA 92354, United States; Department of Physiology and Pharmacology, Loma Linda University, Loma Linda, CA, United States; Department of Anesthesiology, Loma Linda University, Loma Linda, CA, United States; Corresponding authors.
Sheng Chen
Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, 88 Jiefang Road, Hangzhou, Zhejiang 310009, China; Corresponding authors.
Summary: Background: Neuroinflammation and blood coagulation responses in cerebrospinal fluid (CSF) contribute to the poor outcome associated with subarachnoid haemorrhage (SAH). We explored the role of caspase-1-mediated inflammasome activation on extrinsic blood coagulation in CSF after SAH. Methods: Post-SAH proteomic changes and correlation between caspase-1 with extrinsic coagulation factors in human CSF after SAH were analysed. Time course and cell localisation of brain inflammasome and extrinsic coagulation proteins after SAH were explored in a rat SAH model. Pharmacological inhibition of caspase-1 via VX-765 was used to explore the role of caspase-1 in blood clearance and CSF circulation after SAH in rats. Primary astrocytes were used to evaluate the role of caspase-1 in haemoglobin-induced pyroptosis and tissue factor (TF) production/release. Findings: Neuroinflammation and blood coagulation activated after SAH in human CSF. The caspase-1 levels significantly correlated with the extrinsic coagulation factors. The activated caspase-1 and extrinsic coagulation initiator TF was increased on astrocytes after SAH in rats. VX-765 attenuated neurological deficits by accelerating CSF circulation and blood clearance through inhibiting pyroptotic neuroinflammation and TF-induced fibrin deposition in the short-term, and improved learning and memory capacity by preventing hippocampal neuronal loss and hydrocephalus in the long-term after SAH in rats. VX-765 reduced haemoglobin-induced pyroptosis and TF production/release in primary astrocytes. Interpretation: Inhibition of caspase-1 by VX-765 appears to be a potential treatment against neuroinflammation and blood coagulation in CSF after SAH. Funding: This study was supported by National Institutes of Health of United States of America, and National Natural Science Foundation of China.
