Senescent hepatocytes enhance natural killer cell activity via the CXCL-10/CXCR3 axis.

Abstract

Cellular senescence and natural killer (NK) cells play an important role in liver diseases. Chemokines, a component of the senescence-associated secretory phenotype, can recruit NK cells and are involved in the development of various liver diseases. The effect of the C-X-C motif chemokine ligand (CXCL)-9, −10, −11/C-X-C motif chemokine receptor (CXCR)3 axis in senescent hepatocytes remains unknown. The chemokines secreted by senescent hepatocytes, the contribution of the CXCL-9, −10, −11/CXCR3 axis to the migration of NK cells, and the effect of senescent hepatocytes on the function of NK cells were investigated in the present study. The results demonstrated significantly increased levels of C-C motif chemokine ligand 2 and CXCL-1, −2 and −10 in the supernatant of senescent AML12 cells. Despite increased mRNA expression of CXCL-9, −10, and −11 in these cells, western blotting revealed significantly enhanced expression of only CXCL-10. The expression of CXCR3 on the surface of NK cells stimulated by senescent AML12 cells was upregulated (fold change, >3). Following incubation with the supernatant of senescent hepatocytes, both CD107a and interferon γ expression in NK cells increased by >2.5-fold. The cytotoxic effect of NK cells was notably higher stimulated by senescent AML12 cells. Chemotaxis and blocking assays demonstrated that the senescent hepatocytes enhanced the migration of NK cells via the CXCL-10/CXCR3 axis. The present study suggests that senescent hepatocytes secrete various chemokines, including CXCL-10, resulting in the upregulation and activation of CXCR3 in NK cells and the enhancement of NK cell migration via the CXCL-10/CXCR3 axis.