Neutrophil extracellular trap-borne C3-driven endothelial dysfunction in Klebsiella pneumoniae liver abscess

Klebsiella pneumoniae (K. pneumoniae) liver abscess (KPLA) is a severe bacterial infection that is frequently complicated by intrahepatic thrombophlebitis and extrahepatic metastatic infections leading to high mortality rates. This study investigates the role of neutrophil extracellular traps (NETs) in endothelial injury and disease progression in KPLA. Our findings reveal that KPLA patients with intrahepatic thrombophlebitis are more prone to developing sepsis and extrahepatic migratory infections. K. pneumoniae induces NET formation via the TLR4-PI3Kα-AKT signaling pathway, and C3 deposition on NETs significantly contributes to endothelial injury. In a KPLA mouse model, increased C3 levels were observed in the liver, with NETs carrying substantial amounts of C3, disrupting the endothelial barrier and exacerbating liver injury. Treatment with the C3 inhibitor AMY-101 reduced C3 deposition on NETs, alleviated endothelial damage, significantly improved survival, and reduced extrahepatic dissemination, inflammatory infiltration, and lung injury while also suppressing systemic inflammation. Our findings underscore the pivotal role of C3 in NET-mediated endothelial damage and the pathogenesis of KPLA. Thus, targeting C3 deposition on NETs may be a promising therapeutic strategy to reduce endothelial injury, thrombosis, and extrahepatic infections in KPLA without compromising neutrophil antimicrobial function.肺炎克雷伯菌（Klebsiella pneumoniae）肝脓肿（KPLA）是一种严重的细菌感染性疾病，常并发肝内血栓性静脉炎及肝外转移性感染，病死率较高。本研究探讨了中性粒细胞胞外陷阱（neutrophil extracellular traps, NETs）在KPLA内皮损伤与疾病进展中的作用。研究结果显示，合并肝内血栓性静脉炎的KPLA患者更易发生脓毒症及肝外迁移性感染。肺炎克雷伯菌可通过TLR4-PI3Kα-AKT信号通路诱导NET形成，而NET表面的补体C3（complement C3）沉积可显著加重内皮损伤。在KPLA小鼠模型中，肝脏内C3水平升高，且NETs携带大量C3，可破坏内皮屏障并加剧肝损伤。使用补体C3抑制剂AMY-101干预后，NET表面的C3沉积减少，内皮损伤得以缓解，生存率显著提升，同时肝外播散、炎性浸润及肺损伤均得到改善，并可抑制全身性炎症反应。本研究结果证实了C3在NET介导的内皮损伤及KPLA发病机制中的关键作用。因此，靶向NET表面的C3沉积有望成为一种极具前景的治疗策略，可在不影响中性粒细胞抗菌功能的前提下，减轻KPLA患者的内皮损伤、血栓形成及肝外感染。