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Updated: Jul 30, 2026
Controlled Cortical Impact Model for Traumatic Brain Injury
Published on: August 5, 2014
Loss of Wip1 aggravates brain injury after ischaemia/reperfusion by overactivating microglia
Feng Yan1,2, Xiang Cheng3, Ming Zhao3
1Beijing Institute of Brain Disorders, Laboratory of Brain Disorders, Ministry of Science and Technology, Collaborative Innovation Center for Brain Disorders, Capital Medical University, Beijing, China.
Background And Purpose:
The inflammatory response mediated by microglia/macrophages is closely related to cerebral ischaemia/reperfusion injury. Wild-type p53-induced protein phosphatase 1 (Wip1), a serine/threonine phosphatase, is expressed in various tissues. A growing number of reports have suggested that Wip1 is a negative regulator of inflammation in peripheral tissue; however, its role in the central nervous system (CNS) remains unclear. This study aimed to clarify whether Wip1 can inhibit CNS inflammation by regulating microglia/macrophage functions after ischaemic injury.
Methods:
A model of middle cerebral artery occlusion and reperfusion was established in mice. CNS inflammation was simulated by lipopolysaccharide treatment of primary microglia. Laser speckle imaging was used to monitor regional cerebral blood flow. Behavioural outcomes were assessed with a TreadScan gait analysis system. TTC staining was used to evaluate the infarct volume, and western blotting and immunofluorescence staining were applied to detect the phenotypical transformation of microglia. ELISA was performed to detect the levels of inflammatory factors.
Results:
Wip1 expression was increased after ischaemia/reperfusion. Wip1-knockout (KO) mice displayed more severe brain injury than wild-type mice, as indicated by aggravated motor dysfunction, greater brain infarct volumes and higher expression of inflammatory cytokines (interleukin-6 and tumour necrosis factor alpha) in the brain. We also found that Wip1 depletion increased microglial/macrophage activation in both in vitro and in vivo models, which all showed activation of microglia/macrophages. Lentivirus-Ppm1d reversed the injury induced by Wip1-KO.
Conclusions:
Our results suggest that Wip1 may inhibit neuroinflammation by inhibiting microglial/macrophage activation after brain ischaemia/reperfusion injury.
Insights
Wild-type p53-induced protein phosphatase 1 (Wip1) inhibits neuroinflammation by reducing microglial activation following brain ischaemia/reperfusion injury. Wip1 deficiency exacerbates brain damage and inflammatory responses in mice.
Area of Science:
- Neuroscience
- Immunology
- Molecular Biology
Background:
- Microglia/macrophages mediate inflammatory responses crucial in cerebral ischaemia/reperfusion injury.
- Wild-type p53-induced protein phosphatase 1 (Wip1) is a serine/threonine phosphatase known to negatively regulate peripheral inflammation.
- The role of Wip1 in central nervous system (CNS) inflammation remains largely unexplored.
Purpose of the Study:
- To investigate whether Wip1 can suppress CNS inflammation.
- To determine if Wip1 regulates microglia/macrophage function post-ischaemic injury.
Main Methods:
- Established a middle cerebral artery occlusion and reperfusion mouse model.
- Utilized laser speckle imaging, TreadScan gait analysis, and TTC staining for physiological and behavioural assessments.
- Employed western blotting, immunofluorescence, and ELISA to analyze microglial phenotype and inflammatory cytokine levels.
Main Results:
- Wip1 expression increased post-ischaemia/reperfusion.
- Wip1-knockout mice showed exacerbated brain injury, motor dysfunction, and elevated inflammatory cytokines (IL-6, TNF-α).
- Wip1 depletion enhanced microglial/macrophage activation in vitro and in vivo; lentivirus-mediated Wip1 restoration reversed these effects.
Conclusions:
- Wip1 acts as a negative regulator of neuroinflammation.
- Wip1 inhibits microglia/macrophage activation following brain ischaemia/reperfusion injury.
