Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, China.
Key Laboratory of Clinical Pharmacology of Antibiotics, National Health and Family Planning Commission, Shanghai, China.
Front Cell Infect Microbiol. 2022 Sep 29;12:1005392. doi: 10.3389/fcimb.2022.1005392. eCollection 2022.
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.
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.
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.
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.
败血症被认为是一种对感染有反应的危及生命的器官功能障碍综合征。细胞焦亡是一种独特的程序性细胞死亡形式，其特征是炎症细胞因子的分泌。最近，越来越多的研究探讨了败血症和细胞焦亡之间的关系。适当的细胞焦亡有助于控制败血症中的感染，但过度的细胞焦亡可能会导致免疫紊乱。本研究旨在使用全基因组技术鉴定与细胞焦亡相关的基因生物标志物及其与免疫微环境的关系。
下载训练数据集 GSE154918 和验证数据集 GSE185263 进行生物信息学分析。在败血症（包括感染性休克）和健康样本之间鉴定差异表达的与细胞焦亡相关的基因（DEPRGs）。进行基因集富集分析（GSEA）以探索基因功能。使用 CIBERSORT 工具量化浸润免疫细胞，并研究差异浸润免疫细胞与 DEPRG 表达之间的相关性。此外，基于多变量 Cox 回归，该研究还利用随机森林（RF）模型筛选生物标志物。
共鉴定出 12 个 DEPRGs。PLCG1 的表达水平持续显著降低，而 NLRC4 的表达水平从对照组到败血症再到感染性休克逐渐升高。GSEA 发现一个 DEPRG（PLCG1）参与了 T 细胞受体信号通路，并且许多与 T 细胞相关的免疫特征基因集被富集。败血症组浆细胞、T 细胞 CD4 记忆激活和一些固有细胞的比例明显高于健康组，而 T 细胞 CD8、T 细胞 CD4 记忆静止、T 细胞调节（Tregs）和 NK 细胞的比例较低。此外，CASP4 与中性粒细胞呈正相关，与 T 细胞 CD4 记忆静止和 Tregs 呈负相关。最后，鉴定出两个生物标志物（CASP4 和 PLCG1），并构建了一个用于诊断的列线图模型，其 AUC 值为 0.998。
本研究鉴定出两个潜在的与细胞焦亡相关的诊断基因 CASP4 和 PLCG1，并探讨了 DEPRGs 与免疫微环境之间的关系。此外，我们的研究表明，一些 DEPRGs 与能够调节细胞焦亡的一些代表性免疫细胞具有较好的相关性。
