The Ninj1/Dusp1 Axis Contributes to Liver Ischemia Reperfusion Injury by Regulating Macrophage Activation and Neutrophil Infiltration

Abstract

Background & Aims

Liver ischemia-reperfusion (IR) injury represents a major risk factor in both partial hepatectomy and liver transplantation. Nerve injury–induced protein 1 (Ninj1) is widely recognized as an adhesion molecule in leukocyte trafficking under inflammatory conditions, but its role in regulating sterile inflammation during liver IR injury remains unclear.

Methods

Myeloid Ninj1-deficient mice were generated by bone marrow chimeric models using Ninj1 knockout mice and wild-type mice. In vivo, a liver partial warm ischemia model was applied. Liver injury and hepatic inflammation were investigated. In vitro, primary Kupffer cells (KCs) isolated from Ninj1 knockout and wild-type mice were used to explore the function and mechanism of Ninj1 in modulating KC inflammation upon lipopolysaccharide stimulation.

Results

Ninj1 deficiency in KCs protected mice against liver IR injury during the later phase of reperfusion, especially in neutrophil infiltration, intrahepatic inflammation, and hepatocyte apoptosis. This prompted ischemia-primed KCs to decrease proinflammatory cytokine production. In vitro and in vivo, using small-interfering RNA against dual-specificity phosphatase 1 (DUSP1), we found that Ninj1 deficiency diminished the inflammatory response in KCs and neutrophil infiltration through DUSP1-dependent deactivation of the c-Jun-N-terminal kinase and p38 pathways. Sivelestat, a neutrophil elastase inhibitor, functioned similarly to Ninj1 deficiency, resulting in both mitigated hepatic IR injury in mice and a more rapid recovery of liver function in patients undergoing liver resection.

Conclusions

The Ninj1/Dusp1 axis contributes to liver IR injury by regulating the proinflammatory response of KCs, and influences neutrophil infiltration, partly by subsequent regulation of C-X-C motif chemokine ligand 1 (CXCL1) production after IR.

Graphical abstract