Institute of Molecular Biomedicine, Faculty of Medicine, Comenius University, Sasinkova 4, 811 08 Bratislava, Slovakia.
Department of Pediatrics, Faculty of Medicine, Comenius University and National Institute of Children's Diseases, Limbová 1, 831 01 Bratislava, Slovakia.
J Leukoc Biol. 2023 Nov 24;114(6):651-665. doi: 10.1093/jleuko/qiad101.
Neutrophil extracellular traps are potent antimicrobial weapons; however, their formation during sterile inflammation is detrimental, and the mechanism of induction is still unclear. Since advanced age is the primary clinical risk factor for poor outcomes in inflammatory diseases, we hypothesized that sterile stimuli, represented by mitochondria, would induce neutrophil extracellular trap formation in an age-dependent manner. Therefore, we analyzed induction of neutrophil extracellular traps in patients grouped according to age or immune status and observed that neutrophils from elderly patients responded to the presence of mitochondria with enhanced neutrophil extracellular trap formation. These neutrophil extracellular traps were also found to be more oxidized and exhibited higher resistance to DNase I degradation. Additionally, a higher concentration of residual neutrophil extracellular traps was detected in the plasma of the elderly. This plasma was capable of priming neutrophils through TLR9-mediated signaling, leading to further neutrophil extracellular trap formation, which was successfully inhibited with chloroquine. Finally, in a mouse model of mitochondria-induced acute lung injury, we observed that neutrophils from aged mice displayed impaired chemotactic activity but exhibited a trend of higher neutrophil extracellular trap formation. Thus, we propose that residual neutrophil extracellular traps circulating in the elderly preactivate neutrophils, making them more prone to enhanced neutrophil extracellular trap formation when exposed to mitochondria during sterile inflammation. Further investigation is needed to determine whether this vicious circle could be a suitable therapeutic target.
中性粒细胞胞外诱捕网是一种强有力的抗菌武器；然而，在无菌性炎症中形成的中性粒细胞胞外诱捕网是有害的，其诱导机制仍不清楚。由于高龄是炎症性疾病不良预后的主要临床危险因素，我们假设以线粒体为代表的无菌刺激物会以年龄依赖的方式诱导中性粒细胞胞外诱捕网的形成。因此，我们分析了根据年龄或免疫状态分组的患者中性粒细胞胞外诱捕网的诱导情况，观察到老年患者的中性粒细胞对线粒体的存在反应增强，形成更多的中性粒细胞胞外诱捕网。这些中性粒细胞胞外诱捕网也被发现被氧化得更严重，对 DNase I 的降解有更高的抗性。此外，在老年人的血浆中检测到更高浓度的残留中性粒细胞胞外诱捕网。这种血浆能够通过 TLR9 介导的信号通路使中性粒细胞被预先激活，导致进一步形成中性粒细胞胞外诱捕网，而氯喹可以成功抑制这种形成。最后，在一个由线粒体诱导的急性肺损伤的小鼠模型中，我们观察到老年小鼠的中性粒细胞表现出趋化活性受损，但形成中性粒细胞胞外诱捕网的趋势更高。因此，我们提出，循环在老年人中的残留中性粒细胞胞外诱捕网预先激活中性粒细胞，使它们在无菌性炎症中暴露于线粒体时更容易增强中性粒细胞胞外诱捕网的形成。需要进一步研究以确定这个恶性循环是否可以成为一个合适的治疗靶点。
