Human monocytes undergo functional re-programming during sepsis mediated by hypoxia-inducible factor-1α

Area of Science:

• Immunology
• Molecular Biology
• Critical Care Medicine

Background:

• Sepsis involves a dysregulated inflammatory response to infection, but its cellular and molecular basis in humans is unclear.
• Blood monocytes are crucial for host defense but their role in human sepsis pathogenesis is poorly understood.

Purpose of the Study:

• To investigate the transcriptomic, functional, and mechanistic changes in blood monocytes during human sepsis and recovery.
• To elucidate the role of monocyte functional plasticity in sepsis pathogenesis.

Main Methods:

• Transcriptomic analysis of blood monocytes from sepsis patients and recovered individuals.
• Functional assays to assess monocyte phenotypes, including phagocytosis and antimicrobial activity.
• Mechanistic studies to identify key regulatory pathways, such as hypoxia-inducible factor-1α (HIF1α).

Main Results:

• Monocytes exhibited functional plasticity, transitioning from a pro-inflammatory to an immunosuppressive phenotype during human sepsis.
• Enhanced protective functions, including phagocytosis, antimicrobial activity, and tissue remodeling, were observed in sepsis monocytes.
• Hypoxia-inducible factor-1α (HIF1α) was identified as a key mediator of monocyte functional reprogramming in sepsis.

Conclusions:

• Monocyte functional plasticity is a key feature of human sepsis, with a shift towards immunosuppression and enhanced protective functions.
• HIF1α plays a critical role in mediating this monocyte reprogramming.
• Targeting HIF1α in monocytes presents a potential therapeutic strategy for managing human sepsis.