RESUMEN
This study investigates the molecular mechanisms behind ischaemia/reperfusion (I/R) injury in the brain, focusing on neuronal apoptosis. It scrutinizes the role of the Jun proto-oncogene in apoptosis, involvement of SOCS1 in neural precursor cell accumulation in ischaemic regions, and the upregulation of C-EBPß in the hippocampus following I/R. Key to the study is understanding how Jun controls C-EBPß degradation via SOCS1, potentially offering new clinical treatment avenues for I/R. Techniques such as mRNA sequencing, KEGG enrichment analysis and protein-protein interaction (PPI) in mouse models have indicated involvement of Jun (AP-1) in I/R-induced cerebral damage. The study employs middle cerebral artery occlusion in different mouse models and oxygen-glucose deprivation/reoxygenation in cortical neurons to examine the impacts of Jun and SOCS1 manipulation on cerebral I/R injury and neuronal damage. The findings reveal that I/R reduces Jun expression in the brain, but its restoration lessens cerebral I/R injury and neuron death. Jun activates SOCS1 transcriptionally, leading to C-EBPß degradation, thereby diminishing cerebral I/R injury through the SOCS1/C-EBPß pathway. These insights provide a deeper understanding of post-I/R cerebral injury mechanisms and suggest new therapeutic targets for cerebral I/R injury. KEY POINTS: Jun and SOCS1 are poorly expressed, and C-EBPß is highly expressed in ischaemia/reperfusion mouse brain tissues. Jun transcriptionally activates SOCS1. SOCS1 promotes the ubiquitination-dependent C-EBPß protein degradation. Jun blunts oxygen-glucose deprivation/reoxygenation-induced neuron apoptosis and alleviates neuronal injury. This study provides a theoretical basis for the management of post-I/R brain injury.
RESUMEN
BACKGROUND: This study intends to investigate the potential involvement of E3 ubiquitin ligase COP1 in cerebral ischemia-reperfusion (I/R) injury. METHODS: A mouse model of middle cerebral artery occlusion/reperfusion (MCAO/R) was established, and the ischemic penumbra of mouse brain cortex was collected and subjected to RNA-sequencing (RNA-seq). Primary glial cells, neurons and astrocytes were isolated, and microglia were exposed to oxygen and glucose deprivation/reperfusion (OGD/R). RESULTS: COP1 was poorly expressed in MCAO mice and OGD/R microglia. Restoration of COP1 suppressed the activation of microglia and relieves neuroinflammation in cerebral I/R injury, leading to alleviated brain damage (infraction volume [%]: [31.58⯱â¯2.96] & [12.06⯱â¯1.29], neurological scores: [3.6⯱â¯0.6] & [1.2⯱â¯0.5]). COP1 promoted the ubiquitin-mediated degradation of C/EBPß in microglia. It was further revealed that COP1 attenuated microglia activation and phagocytosis (Ibaâ¯+â¯cells [N/mm2]: 182.68⯱â¯20.89 & 84.57⯱â¯12.08; soma area [µm2]: 78.24⯱â¯8.75 & 59.78⯱â¯7.61) through negative regulation of C/EBPß protein expression. Restoration of C/EBPßnegated the neuroprotective effects of COP1 in vivo. DISCUSSION: This study illuminated a mechanism by which COP1 conferred a neuroprotective role in cerebral I/R injury via enhancing the ubiquitin-mediated degradation of transcriptional factor C/EBPß in microglia.