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

Area of Science:

• Immunology
• Gerontology
• Hematology

Background:

• Aging increases sepsis susceptibility due to immune dysfunction.
• Mechanisms of immune failure in elderly sepsis patients are not fully understood.

Purpose of the Study:

• To comprehensively map bone marrow immune cell changes in aged sepsis using single-cell RNA sequencing.
• To identify key intercellular communication pathways disrupted in aged sepsis.
• To explore therapeutic targets for immune dysfunction in elderly sepsis.

Main Methods:

• Polymicrobial sepsis induced via cecal ligation and puncture (CLP) in young and aged mice.
• Bone marrow analysis using single-cell RNA sequencing and CellChat for intercellular communication inference.
• Assessment of myeloid cell migration using Transwell assays.

Main Results:

• Aged septic mice exhibited worsened organ damage and systemic inflammation.
• Immune cell profiles showed reduced adaptive immunity and increased innate immunity.
• Impaired neutrophil chemotaxis, hyperinflammatory yet exhausted monocytes/macrophages, dysfunctional dendritic cells, disrupted B cell maturation, and altered T cell programs were observed.
• Hematopoietic stem cells (HSCs) expanded in aged sepsis, with impaired Lgals9-Cd44-mediated communication affecting myeloid cell migration.

Conclusions:

• Aged sepsis is characterized by widespread bone marrow immune cell dysfunction.
• Impaired HSC-myeloid communication via the Lgals9-Cd44 axis is a critical mechanism of immune failure in elderly sepsis.
• Targeting the Lgals9-Cd44 axis may restore immune coordination in elderly sepsis, warranting further clinical validation.