Significant difference of differential expression pyroptosis-related genes and their correlations with infiltrated immune cells in sepsis.

Background: Sepsis is regarded as a life-threatening organ dysfunction syndrome that responds to infection. Pyroptosis, a unique form of programmed cell death, is characterized by inflammatory cytokine secretion. Recently, an increasing number of studies have investigated the relationship between sepsis and pyroptosis. Appropriate pyroptosis can help to control infection during sepsis, but an immoderate one may cause immune disorders. The present study aimed to identify pyroptosis-related gene biomarkers and their relationship with the immune microenvironment using the genome-wide technique.

Methods: The training dataset GSE154918 and the validation dataset GSE185263 were downloaded for bioinformatics analysis. Differentially expressed pyroptosis-related genes (DEPRGs) were identified between sepsis (including septic shock) and healthy samples. Gene Set Enrichment Analysis (GSEA) was performed to explore gene function. CIBERSORT tools were applied to quantify infiltrating immune cells, and the correlation between differentially infiltrating immune cells and DEPRG expression was investigated. Furthermore, based on multivariable Cox regression, the study also utilized a random forest (RF) model to screen biomarkers.

Results: In total, 12 DEPRGs were identified. The expression level of PLCG1 was continuously significantly decreased, while the expression level of NLRC4 was elevated from control to sepsis and then to septic shock. GSEA found that one DEPRG (PLCG1) was involved in the T-cell receptor signaling pathway and that many T cell-related immunologic signature gene sets were enriched. The proportions of plasma cells, T cells CD4 memory activated, and some innate cells in the sepsis group were significantly higher than those in the healthy group, while the proportions of T cells CD8, T cells CD4 memory resting, T cells regulatory (Tregs), and NK cells were lower. Additionally, CASP4 was positively correlated with Neutrophils and negatively correlated with T cells CD4 memory resting and Tregs. Lastly, two biomarkers (CASP4 and PLCG1) were identified, and a nomogram model was constructed for diagnosis with area under the curve (AUC) values of 0.998.

Conclusion: This study identified two potential pyroptosis-related diagnostic genes, CASP4 and PLCG1, and explored the correlation between DEPRGs and the immune microenvironment. Also, our study indicated that some DEPRGs were satisfactorily correlated with several representative immune cells that can regulate pyroptosis.