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Characterization of MLKL-mediated Plasma Membrane Rupture in Necroptosis
Published on: August 7, 2018
RIPK3-Dependent Necroptosis Activates MCP-1-Mediated Inflammation in Mice after Intracerebral Hemorrhage
Simei Huang1, Wenjie Hu2, Dongmei Rao1
1Key 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.
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.
Insights
Inhibiting receptor-interacting protein kinase 3 (RIPK3) reduces inflammation and brain damage after intracerebral hemorrhage (ICH). This study found RIPK3 interacts with monocyte chemoattractant protein-1 (MCP-1), suggesting a new therapeutic target for ICH.
Area of Science:
- Neuroscience
- Immunology
- Pathology
Background:
- Receptor-interacting protein kinase 3 (RIPK3)-dependent necroptosis is implicated in intracerebral hemorrhage (ICH) pathology.
- Inhibiting necroptosis may prevent inflammation, a key factor in neurological injury and poor outcomes after ICH.
Purpose of the Study:
- To clarify the association between necroptosis and monocyte chemoattractant protein-1 (MCP-1)-mediated inflammation.
- To identify a potential therapeutic target for ICH treatment.
Main Methods:
- Established an ICH mouse model and administered the RIPK3 inhibitor GSK872.
- Assessed brain edema and neurobehavioral function.
- Utilized Western blotting, immunofluorescence staining, and co-immunoprecipitation to analyze molecular changes and interactions.
Main Results:
- ICH increased RIPK3, phospho-MLKL, MCP-1, phospho-JNK, and IL-6 levels.
- GSK872 treatment reduced these markers, mitigating cerebral edema and improving neurobehavioral function.
- RIPK3 and MCP-1 were found to colocalize and form a complex in ICH brain tissue.
Conclusions:
- An association exists between RIPK3 and MCP-1.
- Inhibiting RIPK3 alleviates MCP-1-mediated inflammation in the context of ICH.
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