Activation of RKIP Binding ASC Attenuates Neuronal Pyroptosis and Brain Injury via Caspase-1/GSDMD Signaling Pathway After Intracerebral Hemorrhage in Mice

被引:41
作者
Gu, Lingui [1 ]
Sun, Mingjiang [1 ]
Li, Ruihao [1 ]
Tao, Yihao [1 ]
Luo, Xu [1 ]
Xu, Jing [1 ]
Wu, Xuan [2 ]
Xie, Zongyi [1 ]
机构
[1] Chongqing Med Univ, Affiliated Hosp 2, Dept Neurosurg, 76 Linjiang Rd, Chongqing 400010, Peoples R China
[2] Zhejiang Univ, Ctr Stem Cell & Regenerat Med, Sch Med, Hangzhou 310058, Peoples R China
基金
芬兰科学院;
关键词
Intracerebral hemorrhage; Neuronal pyroptosis; Brain injury; RKIP; NLRP3; inflammasome; KINASE INHIBITOR PROTEIN; CELL-DEATH; INFLAMMASOME; STROKE;
D O I
10.1007/s12975-022-01009-4
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
Pyroptosis has been proven to be responsible for secondary brain injury after intracerebral hemorrhage (ICH). A recent study reported that Raf kinase inhibitor protein (RKIP) inhibited assembly and activation of inflammasome in macrophages. Our present study aimed to investigate the effects of RKIP on inflammasome-mediated neuronal pyroptosis and underlying neuroprotective mechanisms in experimental ICH. Here, we showed that RKIP expression was decreased both in cerebrospinal fluid (CSF) samples from patients with ICH and in the peri-hematoma tissues after experimental ICH. In mouse ICH model, activation of RKIP remarkably improved neurological deficits, reduced brain water content and BBB disruption, and promoted hematoma absorption at 24 h after ICH, as well as alleviated neuronal degeneration, reduced membrane pore formation, and downregulated pyroptotic molecules NLRP3, caspase-1 P20, GSDMD-N, and mature IL-1 beta. Besides, RKIP activation decreased the number of caspase-1 P20-positive neurons after ICH. However, RKIP inhibitor reserved the neuroprotective effects of RKIP at 24 h following ICH. Moreover, RKIP could bind with ASC, then interrupt the assembly of NLRP3 inflammasome. Mechanistically, inhibiting the caspase-1 by VX-765 attenuated brain injury and suppressed neuronal pyroptosis after RKIP inhibitor-pretreated ICH. In conclusion, our findings indicated that activation of RKIP could attenuate neuronal pyroptosis and brain injury after ICH, to some extent, through ASC/Caspase-1/GSDMD pathway. Thus, RKIP may be a potential target to attenuate brain injury via its anti-pyroptosis effect after ICH.
引用
收藏
页码:1037 / 1054
页数:18
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