Hepatectomy leads to loss of TRAIL-expressing liver NK cells via downregulation of the CXCL9-CXCR3 axis in mice.

Liver-resident natural killer (NK) cells express TNF-related apoptosis-inducing ligand (TRAIL), a critical molecule for NK cell-mediated tumor cell killing. We previously reported that TRAIL expression in liver NK cells decreases markedly after hepatectomy; however, the mechanism underlying this drastic alteration remains unknown. In this study, we assessed the role of chemokine signaling in liver-resident NK cells during the perioperative period of hepatectomy. The expression levels of various chemokine receptors on liver-resident NK cells and their associations with TRAIL expression were analyzed by flow cytometry. The expression of various intrahepatic chemokines/cytokines was analyzed after 70% hepatectomy in mice by quantitative RT-PCR and flow cytometry. We further investigated whether polyinosinic-polycytidylic acid (poly I:C)-induced NK cell activation could ameliorate TRAIL expression in the liver after 70% hepatectomy in CXCR3-/- and wild-type mice. TRAIL+ NK cells strongly and exclusively expressed CXCR3, and the expression of its ligand CXCL9 was significantly decreased in the liver after hepatectomy. The kinetics of hepatic CXCL9 expression resembled the changes in hepatic TRAIL+ NK cells after hepatectomy. Among liver-resident mononuclear cells, CXCL9 was predominantly secreted by macrophages in response to interferon-γ stimulation. Although the administration of poly I:C, an inducer of interferon-γ, increased hepatic CXCL9 levels in both CXCR3-/- and wild-type mice even after hepatectomy, only wild-type mice exhibited the recovery of TRAIL expression on NK cells. Partial hepatectomy remarkably reduced the proportion of TRAIL-expressing NK cells in the liver via the downregulation of the CXCL9-CXCR3 axis in mice. These findings extend our knowledge of the factors contributing to hepatocellular carcinoma recurrence after hepatectomy.