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Neutrophil Extracellular Trap-borne C3-Driven Endothelial Dysfunction in Klebsiella pneumoniae Liver Abscess

ABSTRACT: Klebsiella pneumoniae liver abscess (KPLA) is a severe bacterial infection 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 demonstrate that C3 deposition on NETs significantly contributes to endothelial damage. 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. Molecular analysis revealed that the TLR4-PI3Kα-AKT signaling pathway is crucial in K. pneumoniae-induced NET formation. 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE288691 | GEO | 2025/03/21

REPOSITORIES: GEO

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