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

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Abstract

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-1β. 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.

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Data Availability

The data used in the present study are available from the corresponding author on reasonable request.

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Acknowledgements

We thank Prof. Hong Wang, from Key Laboratory of Diagnostic Medicine Designated by the Ministry of Education, Chongqing Medical University, for providing experimental help.

Funding

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).

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  1. Department of Neurosurgery, The Second Affiliated Hospital, Chongqing Medical University, 76 Linjiang Road, Chongqing, 400010, China

    Lingui Gu, Mingjiang Sun, Ruihao Li, Yihao Tao, Xu Luo, Jing Xu & Zongyi Xie

  2. Center for Stem Cell and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, 310058, China

    Xuan Wu

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Contributions

All authors contributed to the study conception and design. Conceptualization was performed by LG and ZX; material preparation, data collection, and analysis were performed by LG, MS, and YY; methodology and software were performed by LG, YT, and RL. The first draft of the manuscript was written by LG and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Zongyi Xie.

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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. All experimental procedures were implemented according to the National Institutes of Health guide for the care and use of Laboratory Animals and the ARRIVE (Animal Research: Reporting In Vivo Experiments) guidelines and were approved by the Institutional Animal Care and Use Committee of Chongqing Medical University.

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Supplementary file1 (PDF 1581 kb) Supplementary Fig.S1 The delivery efficiency of intraperitoneal administration of Didymin and Lococstatin

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Supplementary file2 (PDF 79 kb) Supplementary Table S1 Summary of experimental groups, sample sizes, and mortality rate in the study

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Gu, L., Sun, M., Li, R. et al. Activation of RKIP Binding ASC Attenuates Neuronal Pyroptosis and Brain Injury via Caspase-1/GSDMD Signaling Pathway After Intracerebral Hemorrhage in Mice. Transl. Stroke Res. 13, 1037–1054 (2022). https://doi.org/10.1007/s12975-022-01009-4

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