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RIPK3-Dependent Necroptosis Activates MCP-1-Mediated Inflammation in Mice after Intracerebral Hemorrhage

  • Author Footnotes
    1 These authors equally contributed to this study.
    Simei Huang
    Footnotes
    1 These authors equally contributed to this study.
    Affiliations
    Key Laboratory of Non‐coding RNA Transformation Research of Anhui Higher Education Institutes, Wannan Medical College, Wuhu 241000, Anhui, China

    Department of Neurology, Wannan Medical College First Affiliated Hospital, Yijishan Hospital, Wuhu 241000, Anhui, China;
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  • Author Footnotes
    1 These authors equally contributed to this study.
    Wenjie Hu
    Footnotes
    1 These authors equally contributed to this study.
    Affiliations
    Department of Neurology, The First Affiliated Hospital of Anhui Medical University, Hefei 230000, Anhui, China;
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  • Dongmei Rao
    Affiliations
    Key Laboratory of Non‐coding RNA Transformation Research of Anhui Higher Education Institutes, Wannan Medical College, Wuhu 241000, Anhui, China

    Department of Neurology, Wannan Medical College First Affiliated Hospital, Yijishan Hospital, Wuhu 241000, Anhui, China;
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  • Xiaodong Wu
    Affiliations
    Department of Psychiatry, Chaohu Hospital of Anhui Medical University, Chaohu 238001, Anhui, China.
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  • Qingqing Bai
    Affiliations
    Key Laboratory of Non‐coding RNA Transformation Research of Anhui Higher Education Institutes, Wannan Medical College, Wuhu 241000, Anhui, China

    Department of Neurology, Wannan Medical College First Affiliated Hospital, Yijishan Hospital, Wuhu 241000, Anhui, China;
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  • Jingye Wang
    Correspondence
    Corresponding authors.
    Affiliations
    Department of Neurology, The First Affiliated Hospital of Anhui Medical University, Hefei 230000, Anhui, China;
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  • Zhaohu Chu
    Correspondence
    Corresponding authors.
    Affiliations
    Key Laboratory of Non‐coding RNA Transformation Research of Anhui Higher Education Institutes, Wannan Medical College, Wuhu 241000, Anhui, China
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  • Yang Xu
    Correspondence
    Corresponding authors.
    Affiliations
    Key Laboratory of Non‐coding RNA Transformation Research of Anhui Higher Education Institutes, Wannan Medical College, Wuhu 241000, Anhui, China

    Department of Neurology, Wannan Medical College First Affiliated Hospital, Yijishan Hospital, Wuhu 241000, Anhui, China;

    Non‐coding RNA Research Center of Wannan Medical College, Wuhu 241000, Anhui, China.
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  • Author Footnotes
    1 These authors equally contributed to this study.

      Highlights

      • Inhibiting RIPK3 by using GSK872 exerted protective effects on ICH.
      • Inhibiting RIPK3 alleviated MCP-1-mediated inflammation after ICH.
      • Interaction of RIPK3 and MCP-1 occurred following ICH.

      Abstract

      Background

      Recent studies have reported that receptor-interacting protein kinase 3 (RIPK3)-dependent necroptosis is related to the pathological process of intracerebral hemorrhage (ICH). Some studies support the view that inhibiting necroptosis is a key mechanism preventing inflammation. Inflammation is a crucial factor contributing to neurological injuries and unfavorable outcomes after ICH. The aim of this study was to clarify the association between necroptosis and monocyte chemoattractant protein-1 (MCP-1)-mediated inflammation and identify a new target for the treatment of ICH. Methods: An ICH model was established in C57BL/6 mice by injecting collagenase IV into the right basal ganglia. The RIPK3 inhibitor GSK872 was administered through intraventricular injection. Then, we assessed brain edema and neurobehavioral function. Western blotting was employed to detect changes in RIPK3, phospho-mixed lineage kinase domain-like protein (p-MLKL), MCP-1, phospho-c-Jun N-terminal kinase (p-JNK) and interleukin 6 (IL-6) levels in the brain tissue. The localization of RIPK3 and MCP-1 was observed using immunofluorescence staining. Co-immunoprecipitation was performed to determine the interaction between RIPK3 and MCP-1. Results: Compared with the sham group, the levels of RIPK3, p-MLKL, MCP-1, p-JNK and IL-6 were increased post-ICH. GSK872 pretreatment significantly reduced RIPK3, p-MLKL, MCP-1, p-JNK and IL-6 expression, accompanied by mitigated cerebral edema and neurobehavioral defects. RIPK3 and MCP-1 colocalized in the perinuclear region after ICH. We detected the formation of the RIPK3-MCP-1 complex in ICH brain tissue. Conclusions: There exerted an association between RIPK3 and MCP-1. The inhibition of RIPK3 alleviated MCP-1-mediated inflammation following ICH.

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