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IL-18BP Alleviates Anxiety-Like Behavior Induced by Traumatic Stress via Inhibition of the IL-18R-NLRP3 Signaling Pathway in a Mouse Model of Hemorrhagic Shock and Resuscitation

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Abstract

Psychological distress and posttraumatic stress, including anxiety, severely influence life quality. Previously, we reported that interleukin-18 (IL-18) was involved in pyroptosis-induced emotional changes in a rodent model of hemorrhagic shock and resuscitation (HSR). Here, we aimed to continue our investigation on the role of IL-18 binding protein (IL-18BP), which exhibits excellent anti-inflammatory effects as an IL-18 negative regulator. Mice were administered with an intraperitoneal injection of IL-18BP after HSR exposure and anxiety-like behavior was examined using the open-field test and elevated plus maze test. Moreover, the following variables post-HSR were measured: (1) the activation of astrocytes; (2) pyroptosis-associated factors including cleaved caspase-1, GSDMD, IL-18; (3) the roles of IL-18 receptor (IL-18R)-NOD-like receptor pyrin domain-containing-3 (NLRP3) signal with the application of the NLRP3 specific agonist or astrocyte-specific NLRP3 knockout mice. IL-18BP administration remarkably alleviated HSR-induced anxiety-like behavior, astrocytic activation, and increases in pyroptosis-associated factors, while NLRP3 agonist nigericin partially reversed IL-18BP-induced neuroprotective effects. Astrocyte-specific NLRP3 knockout mice exhibited relatively less anxiety-like behavior. Similarly, IL-18BP exhibited an anti-pyroptosis effect in astrocytes in an in vitro model of low oxygen-glucose deprivation. These findings offer unique perspectives on HSR-induced posttraumatic stress and indicate that inhibition of IL-18R–NLRP3 signal via IL-18BP can attenuate astrocytic activation and pyroptosis, broadening the therapeutic landscape for patients with psychological distress and posttraumatic stress.

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All data generated or analyzed during this study are included in this published article and its supplementary information files.

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Acknowledgements

We want to thank Dr. Xiao-Chun Zhao and Xiao-Ming Li for the critical reading of the manuscript.

Funding

This study was supported by the National Natural Science Foundation of China (No. 81701296, 82171455) and the Natural Science Foundation of Hebei Province (No. H2021110004).

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Author notes

  1. Li-Min Zhang and Dong-Xue Zhang contributed equally to this work

Authors and Affiliations

  1. Department of Anesthesiology, Hebei Province Cangzhou Hospital of Integrated Traditional and Western Medicine (Cangzhou No.2 Hospital), Cangzhou, China

    Li-Min Zhang

  2. Hebei Key Laboratory of Integrated Traditional and Western Medicine in Osteoarthrosis Research (Preparing), Cangzhou, China

    Li-Min Zhang

  3. Department of Gerontology, Cangzhou Central Hospital, Cangzhou, China

    Dong-Xue Zhang

  4. Department of Anesthesiology, Cangzhou Central Hospital, Hebei Medical University, Cangzhou, China

    Rong-Xin Song, Yue Xin & Yan Li

  5. Anesthesia and Trauma Research Unit, Hebei Province Cangzhou Hospital of Integrated Traditional and Western Medicine (Cangzhou No.2 Hospital), Cangzhou, China

    Jin-Meng Lv & Lu-Ying Wang

  6. Department of Neurosurgery, Cangzhou Central Hospital, Hebei Medical University, Cangzhou, China

    Zhi-You Wu & Hui-Tao Miao

  7. Department of Anesthesiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China

    Yan-Bo Zhou & Wei Zhang

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Contributions

Design of the study: Li-Min Zhang

Editing the manuscript: Dong-Xue Zhang, Li-Min Zhang, Wei Zhang

Statistical analysis: Li-Min Zhang, Dong-Xue Zhang

Experiment and data collection: Dong-Xue Zhang, Rong-Xin Song, Zhi-You Wu, Yan-Bo Zhou, Wei Zhang, Jin-Meng Lv, Lu-Ying Wang, Hui-Tao Miao, Yue Xin, Yan Li

All authors read and approved the final manuscript.

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Correspondence to Li-Min Zhang.

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All animal experiments were approved by the Institutional Animal Care and Use Committees of Cangzhou Central Hospital (2021-010-01[z]) and carried out in accordance with recommendations for the Animal Research: Reporting of In Vivo Experiment (ARRIVE) guidelines.

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Supplementary Information

Appendix Table S1

Key resources table (DOCX 20 kb)

Appendix Table S2

Details of statiscis (DOCX 82 kb)

Appendix Table S3

Details of animal grouping (DOCX 65 kb)

ESM 1

(A) Computer printouts showing the shifting trajectories of each group in the open field test on day 15 after trauma. (B) The time in the central zone for each group on day 15 after HSR. (C) Computer printouts showing the shifting trajectories of each group in the elevated plus maze test on day 15 after trauma. (D) The time spent in the open arm for each group on day 15 after HSR. The Data are presented as the mean ± SD (n =12 per group). P-values are reported in Appendix Table S2. ****P <0.0001, *P <0.05. (E) Representative photomicrographs from positive control (with the first and second antibody) and negative control (with the first but without the second antibody) of GFAP. Scale bar =50 μm (PNG 1530 kb)

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Zhang, LM., Zhang, DX., Song, RX. et al. IL-18BP Alleviates Anxiety-Like Behavior Induced by Traumatic Stress via Inhibition of the IL-18R-NLRP3 Signaling Pathway in a Mouse Model of Hemorrhagic Shock and Resuscitation. Mol Neurobiol 60, 382–394 (2023). https://doi.org/10.1007/s12035-022-03085-x

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  • DOI: https://doi.org/10.1007/s12035-022-03085-x

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