Abstract
BackgroundIn mouse models, natural killer (NK) cells have been shown to exert anti-fibrotic activity via killing of activated hepatic stellate cells (HSC). Chemokines and chemokine receptors critically modulate hepatic recruitment of NK cells. In hepatitis C, the chemokine receptor CXCR3 and its ligands have been shown to be associated with stage of fibrosis suggesting a role of these chemokines in HCV associated liver damage by yet incompletely understood mechanisms. Here, we analyzed phenotype and function of CXCR3 expressing NK cells in chronic hepatitis C.MethodsCirculating NK cells from HCV-infected patients (n = 57) and healthy controls (n = 27) were analyzed with respect to CXCR3 and co-expression of different maturation markers. Degranulation and interferon-γ secretion of CXCR3(+) and CXCR3(−) NK cell subsets were studied after co-incubation with primary human hepatic stellate cells (HSC). In addition, intra-hepatic frequency of CXCR3(+) NK cells was correlated with stage of liver fibrosis (n = 15).ResultsWe show that distinct NK cell subsets can be distinguished based on CXCR3 surface expression. In healthy controls CXCR3(+)CD56Bright NK cells displayed strongest activity against HSC. Chronic hepatitis C was associated with a significantly increased frequency of CXCR3(+)CD56Bright NK cells which showed impaired degranulation and impaired IFN-γ secretion in response to HSC. Of note, we observed intra-hepatic accumulation of this NK cell subset in advanced stages of liver fibrosis.ConclusionWe show that distinct NK cell subsets can be distinguished based on CXCR3 surface expression. Intra-hepatic accumulation of the functionally impaired CXCR3(+)CD56Bright NK cell subset might be involved in HCV-induced liver fibrosis.
Highlights
Hepatitis C Virus (HCV) is a major cause for chronic inflammatory liver disease with variable progression towards liver fibrosis/cirrhosis
Flowcytometric analysis revealed that CD56Dim and CD56Bright natural killer (NK) cells can clearly be separated into CXCR3(+) and CXCR3(2) NK cell subsets (Figure 1A) with frequency of CXCR3(+) NK cells being higher in the CD56Bright sub-population
To further characterize CXCR3(+) and CXCR3(2) NK cell sub-populations we studied the co-expression of known NK
Summary
Hepatitis C Virus (HCV) is a major cause for chronic inflammatory liver disease with variable progression towards liver fibrosis/cirrhosis. Hepatic infiltration of immunocompetent cells, including lymphocytes, is a hallmark of HCV infection, and there is accumulating evidence that this inflammatory infiltrate pivotally modulates immunopathogenesis of hepatitis C. Recruitment of lymphocytes to the liver is importantly regulated via chemokines and chemokine receptors. Chemokines are small molecules involved in the regulation of chemotaxis and tissue extravasation of lymphocytes as well as in modulation of leukocyte function. Chemokines and chemokine receptors critically modulate hepatic recruitment of NK cells. In hepatitis C, the chemokine receptor CXCR3 and its ligands have been shown to be associated with stage of fibrosis suggesting a role of these chemokines in HCV associated liver damage by yet incompletely understood mechanisms. We analyzed phenotype and function of CXCR3 expressing NK cells in chronic hepatitis C
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