Gut-primed neutrophils activate Kupffer cells to promote hepatic injury in mouse sepsis.

ABSTRACT: Sepsis-induced liver injury is common, but the underlying mechanisms remain poorly understood. Given the critical role of gut-liver crosstalk in sepsis, we hypothesize that gut-trained neutrophils, migrating via the portal vein, release neutrophil extracellular traps (NETs) to activate Kupffer cells, thereby exacerbating hepatic injury during sepsis. Here we show that iNOS expression in Kupffer cells increases in septic wild type mice but decreases in PAD4^-/- mice. In vitro, NETs stimulate Kupffer cell IL-6 and TNF release, while conditioned media from NET-treated Kupffer cells induces hepatocyte death. Inhibition of neutrophil elastase and protease-activated receptor-1 (PAR-1) mitigates IL-6 and TNF secretion by Kupffer cells. Ex vivo, portal vein neutrophils from septic mice p

SUBMITTER: Murao A 

PROVIDER: S-EPMC12603279 | biostudies-literature | 2025 Nov

REPOSITORIES: biostudies-literature