Department of Neurosurgery, Medical College of Georgia, Augusta University, Augusta, GA, USA.
Department of Oral Biology, Dental College of Georgia, Augusta University, Augusta, GA, USA.
Sci Adv. 2020 May 29;6(22):eaax8847. doi: 10.1126/sciadv.aax8847. eCollection 2020 May.
Traumatic brain injury (TBI) is a major cause of mortality and morbidity. Preventative measures reduce injury incidence and/or severity, yet one-third of hospitalized patients with TBI die from secondary pathological processes that develop during supervised care. Neutrophils, which orchestrate innate immune responses, worsen TBI outcomes via undefined mechanisms. We hypothesized that formation of neutrophil extracellular traps (NETs), a purported mechanism of microbial trapping, exacerbates acute neurological injury after TBI. NET formation coincided with cerebral hypoperfusion and tissue hypoxia after experimental TBI, while elevated circulating NETs correlated with reduced serum deoxyribonuclease-1 (DNase-I) activity in patients with TBI. Functionally, Toll-like receptor 4 (TLR4) and the downstream kinase peptidylarginine deiminase 4 (PAD4) mediated NET formation and cerebrovascular dysfunction after TBI. Last, recombinant human DNase-I degraded NETs and improved neurological function. Thus, therapeutically targeting NETs may provide a mechanistically innovative approach to improve TBI outcomes without the associated risks of global neutrophil depletion.
创伤性脑损伤（TBI）是死亡率和发病率的主要原因。预防措施可降低受伤发生率和/或严重程度，但三分之一的住院 TBI 患者死于在监督护理期间发生的继发性病理过程。中性粒细胞协调先天免疫反应，通过未定义的机制使 TBI 结果恶化。我们假设中性粒细胞胞外诱捕网（NETs）的形成，一种微生物捕获的假定机制，会加重 TBI 后的急性神经损伤。实验性 TBI 后，NET 形成与脑灌注不足和组织缺氧同时发生，而循环中 NETs 的升高与 TBI 患者血清脱氧核糖核酸酶-1（DNase-I）活性降低相关。功能上，Toll 样受体 4（TLR4）和下游激酶肽基精氨酸脱亚氨酶 4（PAD4）介导 TBI 后的 NET 形成和脑血管功能障碍。最后，重组人 DNase-I 降解 NETs 并改善神经功能。因此，针对 NETs 的治疗可能为改善 TBI 结果提供一种具有创新性的机制方法，而不会带来全血细胞耗竭的相关风险。
