Investigating the Role of Neutrophil Extracellular Traps as a Therapeutic Target in Traumatic Brain Injury: a Systematic Review and Meta-analysis

Abstract Traumatic brain injury (TBI) is a leading cause of morbidity and mortality worldwide, with few treatment options to mitigate secondary injury. Neutrophil extracellular traps (NETs) may present a potential target for therapy. The systematic review objectives were to characterise NET formation as a feature following TBI; assess the effect of NET modulatory strategies on outcomes; and investigate the relative efficacy of NET modulatory methods. A systematic review was performed, with inclusion criteria of pre-clinical or clinical studies using any model or severity of TBI, and any investigation of the pathophysiological role of NETs and/or modulation of NETs for therapeutic benefit. Following search completion, 849 records were identified with 13 studies eligible for inclusion. All 13 studies characterised NET formation in blood and brain tissue from pre-clinical TBI models, whilst four studies also demonstrated NET formation in serum and brain tissue of TBI patients. Meta-analysis (where ≥ 3 studies reported outcomes) identified that NET modulation was associated with significant improvement of outcomes in preclinical studies, in both modified neurological severity score and latency to falls. No difference in efficacy was identified between NET modulatory methods after sub-group analysis. In addition, the overall risk of bias was judged as high in the included studies. This systematic review and meta-analysis demonstrated that NETs present a promising TBI therapeutic target for future clinical validation. However, the high bias limits this systematic review, and further high-quality studies are required to make definitive conclusions about NET utility as a viable therapeutic strategy in TBI.