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.
Key Words
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Article info
Publication history
Published online: November 25, 2021
Accepted:
October 31,
2021
Received in revised form:
October 13,
2021
Received:
August 6,
2021
Identification
DOI: https://doi.org/10.1016/j.jstrokecerebrovasdis.2021.106213
Copyright
© 2021 Elsevier Inc. All rights reserved.
