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Study on pyroptosis-related genes Casp8, Gsdmd and Trem2 in mice with cerebral infarction
Shunli Liang1,2, Linsheng Xu1, Xilin Xin1
1Department of Neurology, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China.
Objective:
Cerebral infarction is the main cause of death in patients with cerebrovascular diseases. Our research aimed to screen and validate pyroptosis-related genes in cerebral infarction for the targeted therapy of cerebral infarction.
Methods And Results:
A total of 1,517 differentially expressed genes (DEGs) were obtained by DESeq2 software analysis. Gene set enrichment analysis results indicated that genes of middle cerebral artery occlusion (MCAO) mice aged 3 months and 18 months were enriched in pyroptosis, respectively. Differentially expressed pyroptosis-related genes (including Aim2, Casp8, Gsdmd, Naip2, Naip5, Naip6 and Trem2) were obtained through intersection of DEGs and genes from pyroptosis Gene Ontology Term (GO:0070269), and they were up-regulated in the brain tissues of MCAO mice in GSE137482. In addition, Casp8, Gsdmd, and Trem2 were verified to be significantly up-regulated in MCAO mice in GSE93376. The evaluation of neurologic function and triphenyltetrazolium chloride staining showed that the MCAO mouse models were successfully constructed. Meanwhile, the expressions of TNF-α, pyroptosis-related proteins, Casp8, Gsdmd and Trem2 in MCAO mice were significantly up-regulated. We selected Trem2 for subsequent functional analysis. OGD treatment of BV2 cell in vitro significantly upregulated the expressions of Trem2. Subsequent downregulation of Trem2 expression in OGD-BV2 cells further increased the level of pyroptosis. Therefore, Trem2 is a protective factor regulating pyroptosis, thus influencing the progression of cerebral infarction.
Conclusions:
Casp8, Gsdmd and Trem2 can regulate pyroptosis, thus affecting cerebral infarction.
Insights
Researchers identified key pyroptosis-related genes, including Trem2, that influence cerebral infarction progression. Downregulating Trem2 exacerbates pyroptosis, indicating its protective role in this condition.
Area of Science:
- Neuroscience
- Molecular Biology
- Immunology
Background:
- Cerebral infarction is a leading cause of death associated with cerebrovascular diseases.
- Targeted therapies for cerebral infarction require a deeper understanding of its underlying molecular mechanisms, particularly the role of programmed cell death pathways.
Purpose of the Study:
- To screen and validate pyroptosis-related genes involved in cerebral infarction.
- To investigate the potential of these genes as therapeutic targets for cerebral infarction.
Main Methods:
- Differential gene expression analysis using DESeq2 software on middle cerebral artery occlusion (MCAO) mouse models.
- Gene set enrichment analysis to identify enriched pathways, including pyroptosis.
- Intersection of differentially expressed genes (DEGs) with pyroptosis-related genes from Gene Ontology.
- Validation of gene expression in MCAO mouse models and in vitro oxygen-glucose deprivation (OGD) BV2 cell models.
- Functional analysis of Trem2 by downregulating its expression in OGD-BV2 cells.
Main Results:
- Identified 1,517 DEGs in MCAO mice, with enrichment in pyroptosis-related pathways.
- Confirmed upregulation of pyroptosis-related genes (Aim2, Casp8, Gsdmd, Naip2, Naip5, Naip6, Trem2) in MCAO mouse brain tissues.
- Demonstrated that Trem2 downregulation in OGD-BV2 cells significantly increased pyroptosis levels, suggesting a protective role for Trem2.
Conclusions:
- Caspase-8 (Casp8), Gasdermin D (Gsdmd), and Triggering receptor expressed on myeloid cells 2 (Trem2) are key regulators of pyroptosis in cerebral infarction.
- Trem2 acts as a protective factor by modulating pyroptosis, thereby influencing the progression of cerebral infarction.
- These findings highlight pyroptosis-related genes as potential targets for novel therapeutic strategies against cerebral infarction.
