Peng Fei, Sheng Chunjia, He Jiayi, Zhou Yena, Qu Yilun, Duan Shuwei, Zhao Yinghua, Xia Jikai, Wu Jie, Cai Guangyan, Wu Lingling, Zhang Chuyue, Chen Xiangmei
School of Medicine, Nankai University, Tianjin, 300071, China.
Department of Nephrology, First Medical Center of Chinese PLA General Hospital, National Key Laboratory of Kidney Diseases, Beijing Key Laboratory of Kidney Diseases Research, National Clinical Research Center for Kidney Diseases, Beijing, 100853, China.
Cell Commun Signal. 2025 May 7;23(1):216. doi: 10.1186/s12964-025-02196-x.
Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis globally and a major cause of renal failure. Immune dysregulation drives its pathogenesis. This study identifies novel genes as potential diagnostic and therapeutic targets, elucidating immune mechanisms in IgAN.
Immune cell infiltration analysis was conducted to explore the abnormal regulation of immune cells in IgAN. Weighted gene co-expression network analysis (WGCNA) was integrated with protein-protein interaction (PPI) analysis to identify hub genes associated with dendritic cells (DCs) in IgAN. Receiver operating characteristic (ROC) curve analysis and machine learning algorithms were employed to screen for DC-related diagnostic biomarkers from the dataset. Multiple bioinformatics methods were utilized to reveal shared molecular pathways. The findings were further validated through in vivo and vitro intervention experiments.
WGCNA, Cytoscape, and three machine learning models collectively identified hub genes (IKZF1, MPEG1, CCR2, CCR5, and CCR7) that are significantly associated with DC immunity. Among these, IKZF1 was pinpointed as a key hub gene and a potential diagnostic biomarker for DC-related immune responses. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, and gene set enrichment analysis (GSEA) further revealed substantial differences in the biological processes, signaling pathways, and immune characteristics of DCs. RT-qPCR and immunofluorescence analyses confirmed enhanced infiltration of IKZF1 DCs in the tissues of both IgAN mice and anti-Thy1 nephritis rats. Mechanistically, IKZF1 promotes inflammation by mediating the production of pro-inflammatory factors and enhancing antigen presentation in DCs; this effect can be mitigated by siIKZF1 or lenalidomide treatment under LPS-induced inflammatory conditions in vitro. Consistently, treatment with lenalidomide, a molecular degrader of IKZF1, in anti-Thy1 nephritis models effectively alleviated renal damage and reduced inflammatory cell infiltration.
This study delineated key patterns of immune cell infiltration in IgAN and identified diagnostic biomarkers associated with DCs, offering valuable insights into the potential therapeutic targeting of IKZF1 DCs.
免疫球蛋白A肾病（IgAN）是全球最常见的原发性肾小球肾炎，也是肾衰竭的主要原因。免疫失调驱动其发病机制。本研究鉴定了新的基因作为潜在的诊断和治疗靶点，阐明IgAN中的免疫机制。
进行免疫细胞浸润分析以探索IgAN中免疫细胞的异常调节。将加权基因共表达网络分析（WGCNA）与蛋白质-蛋白质相互作用（PPI）分析相结合，以鉴定与IgAN中树突状细胞（DC）相关的枢纽基因。采用受试者工作特征（ROC）曲线分析和机器学习算法从数据集中筛选DC相关的诊断生物标志物。利用多种生物信息学方法揭示共同的分子途径。通过体内和体外干预实验进一步验证研究结果。
WGCNA、Cytoscape和三种机器学习模型共同鉴定出与DC免疫显著相关的枢纽基因（IKZF1、MPEG1、CCR2、CCR5和CCR7）。其中，IKZF1被确定为关键枢纽基因和DC相关免疫反应的潜在诊断生物标志物。基因本体论（GO）、京都基因与基因组百科全书（KEGG）通路分析和基因集富集分析（GSEA）进一步揭示了DC在生物学过程、信号通路和免疫特征方面的显著差异。RT-qPCR和免疫荧光分析证实，IKZF1 DC在IgAN小鼠和抗Thy1肾炎大鼠的组织中浸润增强。机制上，IKZF1通过介导促炎因子的产生和增强DC中的抗原呈递来促进炎症；在体外LPS诱导的炎症条件下，siIKZF1或来那度胺处理可减轻这种作用。同样，在抗Thy1肾炎模型中，用IKZF1的分子降解剂来那度胺治疗可有效减轻肾损伤并减少炎性细胞浸润。
本研究描绘了IgAN中免疫细胞浸润的关键模式，并鉴定了与DC相关的诊断生物标志物，为IKZF1 DC的潜在治疗靶点提供了有价值的见解。
