Hepatocytes and neutrophils cooperatively suppress bacterial infection by differentially regulating lipocalin‐2 and neutrophil extracellular traps

Lipocalin-2 (LCN2)/neutrophil gelatinase-associated lipocalin (NGAL), a key anti-bacterial protein, are highly elevated in patients with end-stage liver disease that is often associated with bacterial infection. LCN2 is expressed at high levels in both hepatocytes and neutrophils; however, how hepatocyte- and neutrophil-derived LCN2 cooperate to combat bacterial infection remains unclear. Here by studying hepatocyte- and myeloid-specific Lcn2 knockout mice in two models of systemic and local Klebsiella pneumoniae infections, we demonstrated that hepatocytes played a critical role in controlling systemic infection by secreting LCN2 protein into the circulation post intraperitoneal injection of bacteria, whereas neutrophils were more important in combating lung local infection by carrying LCN2 in their specific granules to the local infection site post intratracheal intubation of bacteria. Both hepatocyte- and myeloid cell-derived LCN2 were required against bacterial infection in peritoneal cavity and liver necrotic areas post intraperitoneal injection of Klebsiella pneumoniae. LCN2/NGAL protein was detected in neutrophil extracellular traps (NETs) in activated neutrophils from mice and humans. Disruption of the Lcn2 gene in neutrophils abolished LCN2 on NETs, whereas deletion of this gene in hepatocytes did not affect LCN2 protein on NETs. Genetic deletion of the Lcn2 gene globally or specifically in neutrophils did not affect NET formation, but reduced the bactericidal effect of NETs in vitro. Finally, NGAL positive NETs were detected in the liver from patients with various types of liver diseases. Conclusion Both hepatocytes and neutrophils combat bacterial infection through the production of LCN2. Extracellular LCN2 secreted by hepatocytes limits systemic bacterial infection; whereas neutrophils carry LCN2 protein to the local site and against local bacterial infection through NETs.