Long Qiuyue, Song Shixu, Li Jiwei, Gan Jialing, Yang Shuoqi, Li Boyu, Ye Hongli, Zheng Binghan, Wu Fangfang, Yu Zhichen, Wu Jing, Ding Linyu, Jiang Mingzheng, Hu Xiaoyi, Gao Zhancheng, Zheng Yali
Department of Respiratory, Critical Care and Sleep Medicine, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361101, China.
Institute of Chest and Lung Diseases, Xiamen University, Xiamen 361101, China.
Theranostics. 2025 Jul 11;15(16):7990-8011. doi: 10.7150/thno.112339. eCollection 2025.
Myeloid-derived suppressor cells (MDSCs) play a critical role in inducing T-cell lymphopenia in sepsis, and the highly heterogeneous MDSCs necessitate the identification of key molecules within these cells. By integrating bulk and single-cell transcriptomic sequences, we identified the critical molecular and MDSC subpopulation in pneumonia-induced sepsis (PIS) models. Through fluorescence-activated cell sorting (FACS) technology, we isolated the primary target subset to evaluate its immunosuppressive potential via T-cell proliferation assays, and investigate the underlying cellular and molecular mechanisms. To assess the immunological consequences of molecular interventions (pharmacologic blockade and shRNA-mediated knockdown), we employed a "two-hit" experimental model to monitor T-cell-aassociated immune responses and hosts' outcomes following secondary infection. Futhermore, we collected and analyzed clinical samples to support of translating the cellular and molecular concept to human context. We confirmed the specific enrichment of arginase-2 (ARG2) in CXCR2 MDSCs, which expanded during sepsis and drove immunosuppression via ARG2-mediated arginine depletion. The blockade of ARG2 and arginine supplements improved the proliferation and decreased apoptosis of CD4 T cells. In PIS models, both ARG2 inhibition and knockdown regained CD4 T cells in lung and bone marrow sites, thus enhancing host's resistance to secondary infections caused by opportunistic pathogens. Further mechanistic investigations indicated p38-MAPK as a critical regulator of the protein stability of the immunosuppressive molecule ARG2 in CXCR2 MDSCs, particularly in response to lipopolysaccharide (LPS) stimulation. In the human context, we revealed that CXCR2 MDSC increased in peripheral in septic patients and correlated significantly to lymphopenia and elevated ARG2 levels. Sepsis stimulated p38-MAPK signaling and expanded ARG2-enriched CXCR2 MDSCs to mediate septic lymphopenia via arginine depletion. The ARG2 inhibition restored T-cell immunity against secondary infection in septic immunosuppressed hosts. These findings identified CXCR2 MDSC-derived ARG2 as a promising target of immune enhancement therapy in sepsis.
髓系来源的抑制细胞（MDSCs）在脓毒症诱导的T细胞淋巴细胞减少中起关键作用，高度异质性的MDSCs需要鉴定这些细胞内的关键分子。通过整合批量和单细胞转录组序列，我们在肺炎诱导的脓毒症（PIS）模型中鉴定了关键分子和MDSC亚群。通过荧光激活细胞分选（FACS）技术，我们分离出主要目标亚群，通过T细胞增殖试验评估其免疫抑制潜力，并研究潜在的细胞和分子机制。为了评估分子干预（药物阻断和shRNA介导的敲低）的免疫后果，我们采用了“两次打击”实验模型来监测二次感染后与T细胞相关的免疫反应和宿主结局。此外，我们收集并分析了临床样本，以支持将细胞和分子概念转化到人类情况中。我们证实精氨酸酶-2（ARG2）在CXCR2 MDSCs中特异性富集，其在脓毒症期间扩增并通过ARG2介导的精氨酸消耗驱动免疫抑制。阻断ARG2和补充精氨酸可改善CD4 T细胞的增殖并减少其凋亡。在PIS模型中，抑制和敲低ARG2均可在肺和骨髓部位恢复CD4 T细胞，从而增强宿主对机会性病原体引起的二次感染的抵抗力。进一步的机制研究表明，p38丝裂原活化蛋白激酶（p38-MAPK）是CXCR2 MDSCs中免疫抑制分子ARG2蛋白质稳定性的关键调节因子，特别是在对脂多糖（LPS）刺激的反应中。在人类中，我们发现脓毒症患者外周血中CXCR2 MDSC增加，且与淋巴细胞减少和ARG2水平升高显著相关。脓毒症刺激p38-MAPK信号传导并扩增富含ARG2的CXCR2 MDSCs，通过精氨酸消耗介导脓毒症淋巴细胞减少。抑制ARG2可恢复脓毒症免疫抑制宿主对二次感染的T细胞免疫力。这些发现确定CXCR2 MDSC衍生的ARG2是脓毒症免疫增强治疗的一个有前景的靶点。
