Highlights
- •Patients with PSC showed increased IFNγ serum concentrations and elevated frequencies of hepatic CD56bright NK cells.
- •Less hepatic NK cells and CD8+ T cells expressing cytotoxic effector molecules after deletion of IFNγ in Mdr2−/− mice.
- •Less inflammatory macrophages and more restorative macrophages after genetic deletion of IFNγ.
- •Genetic deletion and blockage of IFNγ in Mdr2−/− mice attenuated liver fibrosis.
Background and Aims
Primary sclerosing cholangitis (PSC) is an idiopathic, chronic cholestatic liver disorder
characterized by biliary inflammation and fibrosis. Increased numbers of intrahepatic
interferon-γ- (IFNγ) producing lymphocytes have been documented in patients with PSC,
yet their functional role remains to be determined.
Methods
Liver tissue samples were collected from patients with PSC. The contribution of lymphocytes
to liver pathology was assessed in Mdr2−/− x Rag1−/− mice, which lack T and B cells, and following depletion of CD90.2+ or natural killer (NK)p46+ cells in Mdr2−/− mice. Liver pathology was also determined in Mdr2−/− x Ifng−/− mice and following anti-IFNγ antibody treatment of Mdr2−/− mice. Immune cell composition was analysed by multi-colour flow cytometry. Liver
injury and fibrosis were determined by standard assays.
Results
Patients with PSC showed increased IFNγ serum levels and elevated numbers of hepatic
CD56bright NK cells. In Mdr2−/− mice, hepatic CD8+ T cells and NK cells were the primary source of IFNγ. Depletion of CD90.2+ cells reduced hepatic Ifng expression, NK cell cytotoxicity and liver injury similar to Mdr2−/− x Rag1−/− mice. Depletion of NK cells resulted in reduced CD8+ T cell cytotoxicity and liver fibrosis. The complete absence of IFNγ in Mdr2−/−x Ifng−/− mice reduced NK cell and CD8+ T cell frequencies expressing the cytotoxic effector molecules granzyme B and TRAIL
and prevented liver fibrosis. The antifibrotic effect of IFNγ was also observed upon
antibody-dependent neutralisation in Mdr2−/− mice.
Conclusion
IFNγ changed the phenotype of hepatic CD8+ T cells and NK cells towards increased cytotoxicity and its absence attenuated liver
fibrosis in chronic sclerosing cholangitis. Therefore, unravelling the immunopathogenesis
of PSC with a particular focus on IFNγ might help to develop novel treatment options.
Lay summary
Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized
by biliary inflammation and fibrosis, whose current medical treatment is hardly effective.
We observed an increased interferon (IFN)-γ response in patients with PSC and in a
mouse model of sclerosing cholangitis. IFNγ changed the phenotype of hepatic CD8+ T lymphocytes and NK cells towards increased cytotoxicity, and its absence decreased
liver cell death, reduced frequencies of inflammatory macrophages in the liver and
attenuated liver fibrosis. Therefore, IFNγ-dependent immune responses may disclose
checkpoints for future therapeutic intervention strategies in sclerosing cholangitis.
Graphical abstract
Graphical Abstract
Keywords
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Article info
Publication history
Published online: June 04, 2019
Accepted:
May 29,
2019
Received in revised form:
April 29,
2019
Received:
February 8,
2019
Identification
Copyright
© 2019 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
