Tan Liping, Kong Wei, Zhou Kangxing, Wang Shuangan, Liang Jun, Hou Yayi, Dou Huan
Nanjing University, The State Key Laboratory of Pharmaceutical Biotechnology and Jiangsu Key Laboratory of Molecular Medicine, Nanjing, People's Republic of China.
Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, People's Republic of China.
Arthritis Rheumatol. 2025 Apr;77(4):423-438. doi: 10.1002/art.43046. Epub 2024 Nov 20.
Myeloid-derived suppressor cells (MDSCs) contribute to the pathogenesis of systemic lupus erythematosus (SLE), in part due to promoting the survival of plasma cells. FoxO1 expression in monocytic MDSCs (M-MDSCs) exhibits a negative correlation with the SLE Disease Activity Index score. This study aimed to investigate the hypothesis that M-MDSC-specific FoxO1 deficiency enhances aberrant B cell function in aggressive SLE.
We used GEO data sets and clinical cohorts to verify the clinical significance of FoxO1 expression and circulating M-MDSCs. Using Cre-LoxP technology, we generated myeloid FoxO1 deficiency mice (mFoxO1) to establish murine lupus-prone models. The transcriptional stage was assessed by integrating chromatin immunoprecipitation (ChIP)-sequencing with transcriptomic analysis, luciferase reporter assay, and ChIP-quantitative polymerase chain reaction. Methylated RNA immunoprecipitation sequencing, RNA sequencing, and CRISPR-dCas9 were used to identify N-adenosine methylation (mA) modification. In vitro B cell coculture experiments, capmatinib intragastric administration, mA-modulated MDSCs adoptive transfer, and sample validation of patients with SLE were performed to determine the role of FoxO1 on M-MDSCs dysregulation during B cell autoreacted with SLE.
We present evidence that low FoxO1 is predominantly expressed in M-MDSCs in both patients with SLE and lupus mice, and mice with myeloid FoxO1 deficiency (mFoxO1) are more prone to B cell dysfunction. Mechanically, FoxO1 inhibits mesenchymal-epithelial transition factor protein (Met) transcription by binding to the promoter region. M-MDSCs FoxO1 deficiency blocks the Met/cyclooxygenase2/prostaglandin E secretion pathway, promoting B cell proliferation and hyperactivation. The Met antagonist capmatinib effectively mitigates lupus exacerbation. Furthermore, alkB homolog 5 (ALKBH5) targeting catalyzes mA modification on FoxO1 messenger RNA in coding sequences and 3' untranslated regions. The up-regulation of FoxO1 mediated by ALKBH5 overexpression in M-MDSCs improves lupus progression. Finally, these correlations were confirmed in untreated patients with SLE.
Our findings indicate that effective inhibition of B cells mediated by the ALKBH5/FoxO1/Met axis in M-MDSCs could offer a novel therapeutic approach to manage SLE.
髓系来源的抑制性细胞（MDSCs）在系统性红斑狼疮（SLE）的发病机制中起作用，部分原因是其促进浆细胞存活。单核细胞MDSCs（M-MDSCs）中的FoxO1表达与SLE疾病活动指数评分呈负相关。本研究旨在探讨M-MDSC特异性FoxO1缺陷会增强侵袭性SLE中异常B细胞功能这一假说。
我们使用基因表达综合数据库（GEO）数据集和临床队列来验证FoxO1表达及循环M-MDSCs的临床意义。利用Cre-LoxP技术，我们构建了髓系FoxO1缺陷小鼠（mFoxO1）以建立小鼠狼疮易感模型。通过将染色质免疫沉淀（ChIP）测序与转录组分析、荧光素酶报告基因检测及ChIP定量聚合酶链反应相结合来评估转录阶段。使用甲基化RNA免疫沉淀测序、RNA测序及CRISPR-dCas9来鉴定N-腺苷甲基化（mA）修饰。进行体外B细胞共培养实验、卡马替尼灌胃给药、mA调节的MDSCs过继转移及SLE患者样本验证，以确定FoxO1在SLE中B细胞自身反应时对M-MDSCs失调的作用。
我们提供的证据表明，SLE患者和狼疮小鼠的M-MDSCs中均主要表达低水平的FoxO1，且髓系FoxO1缺陷小鼠（mFoxO1）更容易出现B细胞功能障碍。从机制上讲，FoxO1通过与启动子区域结合来抑制间充质-上皮转化因子蛋白（Met）的转录。M-MDSCs的FoxO1缺陷会阻断Met/环氧化酶2/前列腺素E分泌途径，从而促进B细胞增殖和过度活化。Met拮抗剂卡马替尼可有效减轻狼疮病情加重。此外，靶向的alkB同源物5（ALKBH5）催化编码序列和3'非翻译区中FoxO1信使RNA上的mA修饰。M-MDSCs中ALKBH5过表达介导的FoxO1上调可改善狼疮进展。最后，这些相关性在未经治疗的SLE患者中得到证实。
我们的研究结果表明，有效抑制M-MDSCs中由ALKBH5/FoxO1/Met轴介导的B细胞，可能为治疗SLE提供一种新的治疗方法。
