Hong Yiyu, Chen Qiutong, Xie Hua, Ma Mingliu, Gan Siting, Zhang Yuqi, Xu Zhaozhong
Department of Emergency, Zhujiang Hospital, Southern Medical University, Guangzhou, People's Republic of China.
J Inflamm Res. 2025 Aug 9;18:10711-10722. doi: 10.2147/JIR.S515615. eCollection 2025.
Sepsis-induced liver injury (SILI) significantly contributes to mortality, yet its underlying immune mechanisms remain poorly understood. This study aimed to identify key immune-related genes (IRGs) driving T cell-mediated responses in SILI and evaluate their diagnostic potential.
Cecal ligation and puncture (CLP) was performed to establish a murine sepsis model (n=7/group), with sham-operated controls. Serum IL-1β and lactate levels were quantified via ELISA. Public transcriptomic datasets (GSE26440, GSE26378, GSE25504, GSE28750; 180 sepsis vs 53 controls) were analyzed to identify differentially expressed IRGs (DEIRGs). Functional enrichment (GO/KEGG), protein-protein interaction (PPI) networks, and single-cell RNA sequencing (scRNA-seq) were integrated to prioritize T cell-associated genes. Flow cytometry assessed immune cell subsets (CD3+ T cells, CD19+ B cells, NK1.1+ NK cells, F4/80+ macrophages) in murine blood. Liver histopathology (HE staining) and cytokine expression (IL-1β/TNF-α; IHC) were evaluated.
CLP mice exhibited elevated IL-1β (P<0.01) and lactate (P<0.01), confirming metabolic dysfunction and inflammation. Bioinformatics analysis identified 19 DEIRGs, with PPI networks implicating immune regulation (PPI enrichment p=3.35×10-6). Flow cytometry confirmed T cell dominance (65.87% vs 63.85% in controls). scRNA-seq revealed four T cell-linked hub genes (FCER1G, IL2RB, PTGDR, XCL1). Protein-protein interaction (PPI) network analysis demonstrated that these genes form a synergistic regulatory network involving NF-κB, JAK-STAT, and other key pathways, with notable features including the IL2RB-XCL1 positive feedback loop and the opposing effects of PTGDR isoforms (DP1/DP2). Histopathology showed hepatic necrosis and inflammatory infiltration, correlating with upregulated IL-1β/TNF-α (IHC, P<0.05).
FCER1G, IL2RB, PTGDR, and XCL1 are novel T cell-related biomarkers of SILI, offering potential therapeutic targets. The study bridges bioinformatics predictions with experimental validation, advancing understanding of immune dysregulation in sepsis.
脓毒症诱导的肝损伤（SILI）对死亡率有显著影响，但其潜在的免疫机制仍知之甚少。本研究旨在确定驱动SILI中T细胞介导反应的关键免疫相关基因（IRGs），并评估其诊断潜力。
进行盲肠结扎和穿刺（CLP）以建立小鼠脓毒症模型（每组n = 7），并设假手术对照组。通过酶联免疫吸附测定（ELISA）对血清白细胞介素-1β（IL-1β）和乳酸水平进行定量。分析公开的转录组数据集（GSE26440、GSE26378、GSE25504、GSE28750；180例脓毒症患者与53例对照）以鉴定差异表达的IRGs（DEIRGs）。整合功能富集（基因本体论/京都基因与基因组百科全书，GO/KEGG）、蛋白质-蛋白质相互作用（PPI）网络和单细胞RNA测序（scRNA-seq）以对T细胞相关基因进行优先级排序。流式细胞术评估小鼠血液中的免疫细胞亚群（CD3 + T细胞、CD19 + B细胞、NK1.1 + NK细胞、F4/80 +巨噬细胞）。评估肝脏组织病理学（苏木精-伊红染色，HE染色）和细胞因子表达（IL-1β/肿瘤坏死因子-α；免疫组化，IHC）。
CLP小鼠的IL-1β（P < 0.01）和乳酸（P < 0.01）水平升高，证实存在代谢功能障碍和炎症。生物信息学分析鉴定出19个DEIRGs，PPI网络涉及免疫调节（PPI富集p = 3.35×10-6）。流式细胞术证实T细胞占优势（65.87%对对照组的63.85%）。scRNA-seq揭示了四个与T细胞相关的枢纽基因（Fc片段受体IgG1，FCER1G；白细胞介素2受体β链，IL2RB；前列腺素D2受体，PTGDR；趋化因子配体1，XCL1）。蛋白质-蛋白质相互作用（PPI）网络分析表明，这些基因形成了一个涉及核因子κB（NF-κB）、Janus激酶-信号转导和转录激活因子（JAK-STAT）及其他关键途径的协同调节网络，显著特征包括IL2RB-XCL1正反馈环和PTGDR亚型（DP1/DP2）的相反作用。组织病理学显示肝坏死和炎症浸润，与IL-1β/肿瘤坏死因子-α上调相关（免疫组化，P < 0.05）。
FCER1G、IL2RB、PTGDR和XCL1是SILI新的T细胞相关生物标志物，提供了潜在的治疗靶点。本研究将生物信息学预测与实验验证相结合，加深了对脓毒症中免疫失调的理解。
