RIPK3-Dependent Necroptosis Activates MCP-1-Mediated Inflammation in Mice after Intracerebral Hemorrhage |
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| Institution: | 1. Key Laboratory of Non‐coding RNA Transformation Research of Anhui Higher Education Institutes, Wannan Medical College, Wuhu 241000, Anhui, China;2. Department of Neurology, Wannan Medical College First Affiliated Hospital, Yijishan Hospital, Wuhu 241000, Anhui, China;;3. Department of Neurology, The First Affiliated Hospital of Anhui Medical University, Hefei 230000, Anhui, China;;4. Non‐coding RNA Research Center of Wannan Medical College, Wuhu 241000, Anhui, China.;5. Department of Psychiatry, Chaohu Hospital of Anhui Medical University, Chaohu 238001, Anhui, China.;1. Department of Neurosurgery, Wessex Neurological Centre, University Hospital Southampton, Southampton SO16 6YD, UK;2. Human Development and Health, Faculty of Medicine, University of Southampton, Southampton SO17 1BJ, UK;3. Clinical Neurosciences, Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton SO17 1BJ, UK;1. Department of Neurology, Nagoya City University East Medical Center, Aichi, Japan;2. Department of Neurology, Nagoya City Rehabilitation Center, Aichi, Japan;3. Department of Neurology, Nagoya City University Graduate School of Medical Sciences, Aichi, Japan;4. Department of Neurology, Toyokawa City Hospital, Aichi, Japan;5. Department of Radiology, Nagoya City University East Medical Center, Aichi, Japan;6. Department of Radiology, National Center for Geriatrics and Gerontology, Aichi, Japan;1. Department of Neurosciences, Box Hill Hospital, Eastern Health, Level 2, 5 Arnold St, Box Hill, Victoria 3128, Australia;2. Eastern Health Clinical School, Faculty of Medicine, Nursing and Health Sciences, Monash University, Victoria, Australia;1. Department of Medicine, National University Health System, Singapore, 1E Kent Ridge Rd, NUHS Tower Block, Level 9 119228, Singapore;2. Department of Cardiology, National University Heart Centre, National University Health System, Singapore |
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| Abstract: | BackgroundRecent 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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