Neutrophil extracellular traps in sepsis: Trade-off between pros and cons

Sepsis, a life-threatening syndrome driven by dysregulated immune responses to infection, presents significant global health challenges with high mortality rates. Neutrophil extracellular traps (NETs), composed of DNA and antimicrobial proteins, play a dual role in sepsis pathogenesis. While NETs trap pathogens and enhance immune responses via antimicrobial activity and immune cell activation, their overproduction exacerbates tissue damage, coagulopathy, and organ dysfunction. This review explores the mechanisms of NET formation, including suicidal, vital, and noncanonical NETosis, and their regulation through pattern recognition receptors, complement systems, and chemokine signaling. The interplay between NETs and immune cells—such as macrophages, T cells, and platelets - is highlighted, emphasizing NETs' role in both pathogen clearance and inflammatory injury. Excessive NETs contribute to sepsis-associated coagulopathy by activating platelets and damaging endothelial cells, while histones and proteases within NETs mediate cytotoxicity. Emerging therapeutic strategies targeting NETs, such as DNase, PAD4 inhibitors, and anti-inflammatory agents, show promise in preclinical studies but face clinical challenges due to their dual roles and off-target effects. Balancing NETs' protective and pathological functions remains critical for sepsis management. This review aims to provide a comprehensive understanding of NETs in sepsis, offering insights for future research and clinical applications.