Cell death mechanisms in sepsis-associated adaptive immune dysfunction

Area of Science:

• Immunology
• Cell Biology
• Pathophysiology

Background:

• Sepsis is a major cause of mortality, characterized by initial hyperinflammation and subsequent adaptive immune collapse.
• Regulated cell death (RCD) pathways, including apoptosis, pyroptosis, necroptosis, and ferroptosis, critically influence immune cell populations and the inflammatory environment during sepsis.

Purpose of the Study:

• To review the distinct roles of RCD pathways in T cell, B cell, and dendritic cell depletion during sepsis.
• To propose a "cell death decision network" centered on key molecular players that governs lymphocyte fate in sepsis.
• To explore the therapeutic potential of targeting RCD pathways for sepsis immunotherapy.

Main Methods:

• Literature review of RCD pathways in sepsis.
• Analysis of molecular mechanisms governing lymphocyte apoptosis, pyroptosis, necroptosis, and ferroptosis.
• Discussion of emerging immunotherapeutic strategies targeting cell death pathways.

Main Results:

• Apoptosis promotes immunosuppression by eliminating lymphocytes.
• Pyroptosis and necroptosis release DAMPs, exacerbating inflammation and destroying adaptive immune cells.
• Ferroptosis selectively targets metabolically active T cells (CD8+ and T helper cells).
• These RCD pathways converge on a central network involving caspase-8, RIPK1, ROS, and mitochondria, dictating lymphocyte fate.

Conclusions:

• The "cell death decision network" integrates multiple RCD pathways to determine lymphocyte survival or death under septic stress.
• Targeting RCD pathways offers potential for precision immunotherapy in sepsis.
• Successful therapeutic strategies require phase-specific application, biomarker-guided stratification, and cell-type-selective delivery to restore adaptive immunity and improve survival.