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<p>Aging substantially increases susceptibility to sepsis, yet the underlying mechanisms of immune dysfunction in the elderly remain incompletely understood. Polymicrobial sepsis was induced in young and aged male mice via cecal ligation and puncture (CLP). Bone marrow from four groups (Y-Sham, <i>n</i> = 2; Y-CLP, <i>n</i> = 3; A-Sham, <i>n</i> = 2; A-CLP, <i>n</i> = 3) was analyzed by single-cell RNA sequencing and intercellular communication inferred via CellChat. Age-related immune changes were evaluated, and Transwell assays were used to assess myeloid cell migration. Aged septic mice showed worsened organ damage and systemic inflammation, with reduced adaptive (18.7% vs. 41.3%) and increased innate immunity (58.8% vs. 37.7%, A-CLP vs. Y-CLP). Neutrophil chemotaxis was impaired; monocytes and macrophages adopted a hyperinflammatory yet functionally exhausted phenotype; dendritic cells showed increased antigen presentation with diminished mobility; B cell maturation was disrupted with regression to earlier developmental stages; and T cells shifted toward stress-responsive and regulatory programs. We identified a cluster-specific expansion of HSCs in aged sepsis (39.8% vs. 31.2% in A-CLP vs. Y-CLP) with impaired Lgals9–Cd44-mediated intercellular communication. Myeloid cell migration was impaired in A-CLP but partially restored by Lgals9–Cd44 activation. This study presents a comprehensive single-cell map of bone marrow immune dysfunction in aged sepsis and identifies impaired HSC–myeloid communication as a critical mechanism driving immune failure. Therapeutically targeting the Lgals9–Cd44 axis may restore immune coordination in elderly sepsis, although its clinical feasibility and safety remain to be validated.</p>

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Single-cell transcriptomic analysis reveals immune remodeling in bone marrow during aged sepsis

  • 期刊论文

  • 发表日期：

    2025年11月12日

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  • Yijia Lin,
  • Zhiying Zhou,
  • Mingkun Yang,
  • Yingzheng Weng,
  • Zhouxin Yang,
  • Jing Yan

摘要

Aging substantially increases susceptibility to sepsis, yet the underlying mechanisms of immune dysfunction in the elderly remain incompletely understood. Polymicrobial sepsis was induced in young and aged male mice via cecal ligation and puncture (CLP). Bone marrow from four groups (Y-Sham, n = 2; Y-CLP, n = 3; A-Sham, n = 2; A-CLP, n = 3) was analyzed by single-cell RNA sequencing and intercellular communication inferred via CellChat. Age-related immune changes were evaluated, and Transwell assays were used to assess myeloid cell migration. Aged septic mice showed worsened organ damage and systemic inflammation, with reduced adaptive (18.7% vs. 41.3%) and increased innate immunity (58.8% vs. 37.7%, A-CLP vs. Y-CLP). Neutrophil chemotaxis was impaired; monocytes and macrophages adopted a hyperinflammatory yet functionally exhausted phenotype; dendritic cells showed increased antigen presentation with diminished mobility; B cell maturation was disrupted with regression to earlier developmental stages; and T cells shifted toward stress-responsive and regulatory programs. We identified a cluster-specific expansion of HSCs in aged sepsis (39.8% vs. 31.2% in A-CLP vs. Y-CLP) with impaired Lgals9–Cd44-mediated intercellular communication. Myeloid cell migration was impaired in A-CLP but partially restored by Lgals9–Cd44 activation. This study presents a comprehensive single-cell map of bone marrow immune dysfunction in aged sepsis and identifies impaired HSC–myeloid communication as a critical mechanism driving immune failure. Therapeutically targeting the Lgals9–Cd44 axis may restore immune coordination in elderly sepsis, although its clinical feasibility and safety remain to be validated.