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

作者全名："Gu, Lingui; Sun, Mingjiang; Li, Ruihao; Tao, Yihao; Luo, Xu; Xu, Jing; Wu, Xuan; Xie, Zongyi"

作者地址："[Gu, Lingui; Sun, Mingjiang; Li, Ruihao; Tao, Yihao; Luo, Xu; Xu, Jing; Xie, Zongyi] Chongqing Med Univ, Affiliated Hosp 2, Dept Neurosurg, 76 Linjiang Rd, Chongqing 400010, Peoples R China; [Wu, Xuan] Zhejiang Univ, Ctr Stem Cell & Regenerat Med, Sch Med, Hangzhou 310058, Peoples R China"

通信作者："Xie, ZY (通讯作者)，Chongqing Med Univ, Affiliated Hosp 2, Dept Neurosurg, 76 Linjiang Rd, Chongqing 400010, Peoples R China."

来源：TRANSLATIONAL STROKE RESEARCH

ESI学科分类：NEUROSCIENCE & BEHAVIOR

WOS号：WOS:000776973100001

JCR分区：Q1

影响因子：6.9

年份：2022

卷号：　

期号：　

开始页：　

结束页：　

文献类型：Article; Early Access

关键词：Intracerebral hemorrhage; Neuronal pyroptosis; Brain injury; RKIP; NLRP3 inflammasome

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."

基金机构：Kuanren Talents Program of the Second Affiliated Hospital of Chongqing Medical University [201959]; Venture & Innovation Support Program for Chongqing Overseas Returnees [CX2019156]; Chongqing Science and Health Joint Medical Research Project [2020GDRC006]; Chongqing Postgraduate Scientific Research Innovation Project [CYS20198]

基金资助正文："This work was supported by the Kuanren Talents Program of the Second Affiliated Hospital of Chongqing Medical University (No. 201959), Venture & Innovation Support Program for Chongqing Overseas Returnees (No. CX2019156), Chongqing Science and Health Joint Medical Research Project (No. 2020GDRC006), and Chongqing Postgraduate Scientific Research Innovation Project (No.CYS20198)."