Highly activated TRAIL+ CD56bright NK cells are associated with the liver damage in HBV-LC patients

Abstract

Background: Chronic hepatitis B-related liver cirrhosis(HBV-LC)is the most common cirrhosis in China, which is characterized as liver damage and high mortality. We aim to investigate the characteristics of TRAIL⁺NK cells in patients with HBV-LC and their relationship with liver damage in patients with HBV-LC.

Methods: Thirty cases each of chronic hepatitis B (CHB), HBV-related compensated liver cirrhosis (HBV-CLC) and HBV-related decompensated liver cirrhosis (HBV-DLC) patients were recruited in this study. Thirty age-and sex-matched healthy individuals were recruited as healthy controls (HCs). NK cell phenotypes were determined using flow cytometry. Serum chemokine concentrations were ascertained using the CBA Flex set. Cell apoptosis was analyzed using the Annexin V-PE/7-AAD apoptosis Kit.

Results: CD56^bright NK cells increased, but CD56^dim NK cells reduced in HBV-LC patients. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) was mainly expressed on CD56^bright NK cells. As the degree of liver damage increased, the frequency and activation of total TRAIL⁺NK cells and TRAIL⁺NK cell subsets continued to increase, especially in the HBV-LC patients. Furthermore, the difference in frequency and activation of total TRAIL⁺NK cells between the HBV-CLC and HBV-DLC groups was mainly due to the highly activation and increase of TRAIL⁺CD56^bright NK cells. With the increasing degree of liver damage, CXCR3-associated chemokines (including CXCL9, CXCL10 and CXCL11) were constantly increased, particularly in the HBV-DLC group. The expression of CXCR3 on CD56^bright NK cells was almost 100 % in all enrolled cohorts. CXCR3-associated chemokines were negatively correlated with liver function and positively correlated with fibrosis degree. TRAIL⁺CD56^bright NK cells were negatively correlated with liver function, and positively correlated with fibrosis degree and CXCR3-associated chemokines. The apoptosis of K562 cells and hepatocytes was suppressed partially by the TRAIL-neutralizing antibodies.

Conclusions: The increase of CXCR3-related chemokines (including CXCL9, CXCL10 and CXCL11) might be related to the migration of TRAIL⁺ CD56^bright NK cells to the liver. Highly activated TRAIL⁺ CD56^bright NK cells were associated with the liver damage in HBV-LC patients. These findings may provide new perspectives and theoretical basis for future immunotherapy of HBV-LC patients.

Keywords: CD56(bright) NK cells; HBV-related liver cirrhosis; Liver damage; TRAIL.