Abstract：
The involvement of innate immune mediators to the Zika virus (ZIKV)-induced neuroinflammation is not yet well known. Here, we investigated whether neutrophil extracellular traps (NETs), which are scaffolds of DNA associated with proteins, have the potential to injure peripheral nervous. The tissue lesions were evaluated after adding NETs to dorsal root ganglia (DRG) explants and to DRG constituent cells or injecting them into mouse sciatic nerves. Identification of NET harmful components was achieved by pharmacological inhibition of NET constituents. We found that ZIKV inoculation into sciatic nerves recruited neutrophils and elicited the production of the cytokines CXCL1 and IL-1β, classical NET inducers, but did not trigger NET formation. ZIKV blocked PMA- and CXCL8-induced NET release, but, in contrast, the ZIKV nonstructural protein (NS)-1 induced NET formation. NET-enriched supernatants were toxic to DRG explants, decreasing neurite area, length, and arborization. NETs were toxic to DRG constituent cells and affected myelinating cells. Myeloperoxidase (MPO) and histones were identified as the harmful component of NETs. NS1 injection into mouse sciatic nerves recruited neutrophils and triggered NET release and caspase-3 activation, events that were also elicited by the injection of purified MPO. In summary, we found that ZIKV NS1 protein induces NET formation, which causes nervous tissue damages. Our findings reveal new mechanisms leading to neuroinflammation by ZIKV.
摘要：
先天免疫介质与寨卡病毒（ZIKV）诱导的神经炎症的关系尚不清楚。这里,我们调查了中性粒细胞胞外诱捕网(NET)，它们是与蛋白质相关的DNA支架，有可能损伤周围神经。在将NETs添加到背根神经节（DRG）外植体和DRG组成细胞或将其注射入小鼠坐骨神经后，评估组织病变。NET有害成分的鉴定是通过NET成分的药理抑制作用来实现的。我们发现ZIKV接种坐骨神经会招募中性粒细胞并引起细胞因子CXCL1和IL-1β的产生，经典的NET诱导物，但没有触发NET形成。ZIKV阻断了PMA-和CXCL8诱导的NET释放，但是,相比之下,ZIKV非结构蛋白(NS)-1诱导NET形成。NET富集的上清液对DRG外植体有毒，减少神经突面积，长度,和乔木化。NET对DRG组成细胞具有毒性并影响髓鞘细胞。髓过氧化物酶（MPO）和组蛋白被鉴定为NETs的有害成分。NS1注射到小鼠坐骨神经募集中性粒细胞，并触发NET释放和caspase-3激活，通过注射纯化的MPO也引起的事件。总之,我们发现ZIKVNS1蛋白诱导NET形成，导致神经组织损伤。我们的发现揭示了ZIKV导致神经炎症的新机制。
