The “Double-Edged Sword” of Neutrophils in Trauma: From Pathophysiological Mechanisms to Precision Immunomodulation Strategies

Neutrophils occupy a central yet paradoxical position in post-trauma immunity, functioning as both sentinels of host defense and mediators of tissue damage. This review comprehensively examines the spatiotemporal dynamics of neutrophil biology after trauma, ranging from recruitment and effector functions to diverse cell death modalities. We detail how aberrant activation mechanisms, specifically oxidative burst, protease release, and neutrophil extracellular trap formation fuel systemic inflammation, immunothrombosis, and remote organ injury. We also discuss the neutrophil dysfunction-induced immunosuppression and barriers to tissue regeneration. Mechanistically, we dissect the regulatory networks involving NF-κB/MAPK signaling, non-coding RNAs, extracellular vesicles, and metabolic reprogramming. On the clinical front, we evaluate emerging biomarkers and precision therapeutics, such as CXCR2 antagonists and neutrophil extracellular traps inhibitors, designed to recalibrate rather than ablate neutrophil function to balance host defense and tissue repair. We conclude by outlining a future roadmap that leverages single-cell multi-omics and AI to resolve neutrophil heterogeneity and advance personalized interventions for trauma patients.