Nursing Department, Zhejiang Hospital.
Institute of Health Food, Zhejiang Academy of Medical Sciences.
Medicine (Baltimore). 2021 Mar 26;100(12):e24669. doi: 10.1097/MD.0000000000024669.
Neutrophils have crucial roles in defensing against infection and adaptive immune responses. This study aimed to investigate the genetic mechanism in neutrophils in response to sepsis-induced immunosuppression.The GSE64457 dataset was downloaded from the Gene Expression Omnibus database and the neutrophil samples (D3-4 and D6-8 post sepsis shock) were assigned into two groups. The differentially expressed genes (DEGs) were identified. The Short Time-series Expression Miner (STEM) clustering analysis was conducted to select the consistently changed DEGs post sepsis shock. The overlapping genes between the DEGs and the deposited genes associated with immune, sepsis, and immunosuppression in the AmiGO2 and Comparative Toxicogenomics Database were screened out and used for the construction of the protein-protein interaction (PPI) network. The expression of several hub genes in sepsis patients was validated using the PCR analysis. The drugs targeting the hub genes and the therapy strategies for sepsis or immunosuppression were reviewed and used to construct the drug-gene-therapy-cell network to illustrate the potential therapeutic roles of the hub genes.A total of 357 overlapping DEGs between the two groups were identified and were used for the STEM clustering analysis, which generated four significant profiles with 195 upregulated (including annexin A1, ANXA1; matrix metallopeptidase 9, MMP9; and interleukin 15, IL-15) and 151 downregulated DEGs (including, AKT1, IFN-related genes, and HLA antigen genes). Then, a total of 34 of the 151 downregulated DEGs and 39 of the 195 upregulated DEGs were shared between the databases and above DEGs, respectively. The PPI network analysis identified a downregulated module including IFN-related genes. The deregulation of DEGs including AKT1 (down), IFN-inducible protein 6 (IFI6, down), IL-15 (up), and ANXA1 (up) was verified in the neutrophils from patients with sepsis-induced immunosuppression as compared with controls. Literature review focusing on the therapy showed that the upregulation of IL-15, IFN, and HLA antigens are the management targets. Besides, the AKT1 gene was targeted by gemcitabine.These findings provided additional clues for understanding the mechanisms of sepsis-induced immunosuppression. The drugs targeting AKT1 might provide now clues for the management strategy of immunosuppression with the intention to prevent neutrophil infiltration.
中性粒细胞在抗感染和适应性免疫反应中起着至关重要的作用。本研究旨在探讨中性粒细胞对脓毒症诱导免疫抑制的遗传机制。从基因表达综合数据库（Gene Expression Omnibus database）中下载 GSE64457 数据集，并将中性粒细胞样本（脓毒症休克后 D3-4 和 D6-8）分为两组。鉴定差异表达基因（DEGs）。采用短时间序列表达 Miner（Short Time-series Expression Miner，STEM）聚类分析，筛选脓毒症休克后持续变化的 DEGs。筛选 DEGs 与 AmiGO2 和比较毒理学基因组数据库中与免疫、脓毒症和免疫抑制相关的已存入基因之间的重叠基因，并构建蛋白质-蛋白质相互作用（protein-protein interaction，PPI）网络。采用 PCR 分析验证脓毒症患者中几个关键基因的表达。综述了针对关键基因的药物及脓毒症或免疫抑制的治疗策略，并构建了药物-基因-治疗-细胞网络，以说明关键基因的潜在治疗作用。两组之间共鉴定出 357 个重叠 DEGs，用于 STEM 聚类分析，生成了 4 个具有 195 个上调基因（包括膜联蛋白 A1、基质金属蛋白酶 9 和白细胞介素 15）和 151 个下调基因（包括 AKT1、IFN 相关基因和 HLA 抗原基因）的显著谱。然后，数据库中分别共享了下调基因中的 34 个和上调基因中的 39 个与上述 DEGs 重叠。PPI 网络分析鉴定出一个下调的模块，包括 IFN 相关基因。与对照组相比，脓毒症诱导免疫抑制患者中性粒细胞中 AKT1（下调）、IFN 诱导蛋白 6（IFN-inducible protein 6，IFI6，下调）、白细胞介素 15（上调）和膜联蛋白 A1（上调）等 DEGs 的失调得到了验证。文献综述集中于治疗方面，表明白细胞介素 15、IFN 和 HLA 抗原的上调是管理目标。此外，AKT1 基因是吉西他滨的作用靶点。这些发现为理解脓毒症诱导免疫抑制的机制提供了更多线索。针对 AKT1 的药物可能为预防中性粒细胞浸润的免疫抑制管理策略提供新的线索。
