ObjectiveMyeloid‐derived suppressor cells (MDSCs) contribute to the pathogenesis of systemic lupus erythematosus (SLE), in part due to promoting the survival of plasma cells. Forkhead box protein O1 (FoxO1) expression in monocytic MDSCs (M‐MDSCs) exhibits a negative correlation with the SLE Disease Activity Index (SLEDAI) score. This study aimed to investigate the hypothesis that M‐MDSCs specific FoxO1 deficiency enhances aberrant B cell function in aggressive SLE.MethodsWe used GEO datasets and clinical cohorts to verify the FoxO1 expression and circulating M‐MDSCs clinical significance. Using Cre‐LoxP technology, we generated myeloid FoxO1 deficiency mice (mFoxO1‐/‐) to establish murine lupus‐prone models. The transcriptional stage was assessed by integrating ChIP‐seq with transcriptomic analysis, luciferase reporter assay and ChIP‐qPCR. Methylated RNA immunoprecipitation sequencing, RNA sequencing and CRISPR‐dCas9 were used to identify m6A modification. In vitro B cell co‐culture experiments, Capmatinib intragastric administration, m6A‐modulated MDSCs adoptive transfer, and SLE patient sample validation were performed to determine the role of FoxO1 on M‐MDSCs dysregulation during B cell autoreacted with SLE.ResultsWe present evidence that low FoxO1 is predominantly expressed in M‐MDSCs in both SLE patients and lupus mice, and mice with myeloid FoxO1 deficiency (mFoxO1‐/‐) are more prone to B cell dysfunction. Mechanically, FoxO1 inhibits Met transcription by binding to the promoter region. M‐MDSCs FoxO1 deficiency blocks the Met/COX2/PGE2 secretion pathway, promoting B cell proliferation and hyperactivation. Met antagonist Capmatinib effectively mitigates lupus exacerbation. Furthermore, ALKBH5 targeting catalyzes m6A modification on FoxO1 mRNA in CDS and 3'‐UTR regions. Upregulation of FoxO1 mediated by ALKBH5 overexpression in M‐MDSCs improves lupus progression. Finally, these correlations were confirmed in untreated SLE patients.ConclusionOur findings indicate that effective inhibition of B cells mediated by ALKBH5/FoxO1/Met axis in M‐MDSCs could offer a novel therapeutic approach to manage SLE.image

中文翻译：

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M-MDSCs 中的 FoxO1 缺乏加剧了系统性红斑狼疮的 B 细胞功能障碍


目的髓源性抑制细胞 （MDSC） 有助于系统性红斑狼疮 （SLE） 的发病机制，部分原因是促进浆细胞的存活。叉头盒蛋白 O1 （FoxO1） 在单核细胞 MDSC （M-MDSC） 中的表达与 SLE 疾病活动指数 （SLEDAI） 评分呈负相关。本研究旨在探讨 M-MDSCs 特异性 FoxO1 缺陷增强侵袭性 SLE 中异常 B 细胞功能的假设。方法我们使用 GEO 数据集和临床队列来验证 FoxO1 表达和循环 M-MDSCs 的临床意义。使用 Cre-LoxP 技术，我们生成了髓系 FoxO1 缺陷小鼠 （mFoxO1‐/‐） 以建立小鼠狼疮易感模型。通过将 ChIP-seq 与转录组学分析、荧光素酶报告基因检测和 ChIP-qPCR 相结合来评估转录阶段。甲基化 RNA 免疫沉淀测序、 RNA 测序和 CRISPR-dCas9 鉴定 m6A 修饰。进行体外 B 细胞共培养实验、卡马替尼胃内给药、m6A 调节的 MDSCs 过继转移和 SLE 患者样本验证，以确定 FoxO1 对 B 细胞与 SLE 自反应期间 M-MDSCs 失调的作用。结果我们提供的证据表明，低 FoxO1 主要在 SLE 患者和狼疮小鼠的 M-MDSCs 中表达，而患有髓系 FoxO1 缺陷 （mFoxO1‐/‐） 的小鼠更容易发生 B 细胞功能障碍。在机械上，FoxO1 通过与启动子区域结合来抑制 Met 转录。M-MDSCs FoxO1 缺陷阻断 Met/COX2/PGE2 分泌途径，促进 B 细胞增殖和过度激活。Met 拮抗剂 Capmatinib 可有效减轻狼疮恶化。 此外，ALKBH5 靶向催化 CDS 和 3'-UTR 区 FoxO1 mRNA 上的 m6A 修饰。在 M-MDSC 中过表达 ALKBH5 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。结论我们的研究结果表明，在 M-MDSCs 中有效抑制 ALKBH5/FoxO1/Met 轴介导的 B 细胞可以为治疗 SLE 提供一种新的治疗方法。图像