Abstract
Natural killer (NK) cells can induce liver fibrosis remission by killing hepatic stellate cells (HSCs) and producing interferon (IFN)-γ in a mouse model; however, their anti-fibrotic immune-characteristics and regulatory mechanisms by HSCs remain to be determined, especially in livers from HBV-infected liver cirrhosis (LC) patients. We analyzed frequency, phenotype and anti-fibrotic function of hepatic and peripheral NK subsets in 43 HBV-LC patients. We found that hepatic NK subsets from LC patients displayed a decreased frequency, activation status and anti-fibrotic activity compared with those from chronic hepatitis B patients, which were mainly mediated by increased intrahepatic tumour-growth factor (TGF)-β because blockade of TGF-β significantly reversed NK anti-fibrotic function in vitro. In vivo, hepatic NK cells were enriched in proximity to the α-smooth muscle actin (α-SMA+) area within mild fibrosis regions; while in severe fibrotic areas, they were either directly attached to or separated from the α-SMA+ region. NK cells from LC patients could enter HSCs to form emperipolesis (a cell-in-cell structure) and become apoptotic; anti-TGF-β treatment ameliorated this emperipolesis. This finding suggested a novel mechanism by which activated HSCs impair NK cells’ anti-fibrosis capacity through a TGF-β-dependent emperipolesis in LC patients, providing an anti-fibrotic rational by enhancing NK cell activity.
Highlights
Results[6,7]
When the ratio between CD56bright and CD56dim natural killer (NK) subsets was calculated, we found that the ratio of CD56bright/CD56dim in both liver-infiltrating lymphocytes (LILs) and peripheral blood mononuclear cells (PBMCs) was increased significantly in the context of chronic hepatitis B virus (HBV) infection, especially in the blood of liver cirrhosis (LC) patients (Fig. 1e)
The present study demonstrated that hepatic NK cells showed a numerical decrease, phenotypic deactivation, impaired anti-fibrotic activity and close spatial interaction with hepatic stellate cells (HSCs) in HBV-infected LC patients compared with chronic hepatitis B (CHB) patients and healthy control (HC) subjects
Summary
Results[6,7]. Natural killer T- (NKT) cells play dual roles in controlling HSC activation and liver fibrosis by producing both anti-fibrotic and pro-fibrotic cytokines[8,9]. Natural killer (NK) cells, being abundant in the liver and serving as the major innate immune component against infection and tumours[10], play an important role in inhibiting liver fibrosis[11,12] These results were later confirmed in other mouse models of liver fibrosis[13,14,15] and in HCV patients by several clinical studies[14,16,17]. NK cell-derived IFN-γexerts its anti-fibrotic effects by inducing HSC apoptosis and cell cycle arrest[22,23] or by killing activated HSCs via tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and fas ligand (FasL)[17] These findings suggested that NK cells are likely to play an important role in alleviating liver fibrogenesis by interacting HSCs. The mechanisms mentioned above provide some insight into the molecular mechanisms of how NK cells kill HSCs and antagonise fibrosis. Our findings will promote the rational development of immunotherapeutic strategies to enhance NK activity while limiting or abolishing liver fibrosis in chronic HBV infection
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