Interferon-γ-dependent immune responses contribute to the pathogenesis of sclerosing cholangitis in mice
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Interferon-γ-dependent immune responses contribute to the pathogenesis of sclerosing cholangitis in mice. / Ravichandran, Gevitha; Neumann, Katrin; Berkhout, Laura K; Weidemann, Sören; Langeneckert, Annika E; Schwinge, Dorothee; Poch, Tobias; Huber, Samuel; Schiller, Birgit; Hess, Leonard U; Ziegler, Annerose E; Oldhafer, Karl J; Barikbin, Roja; Schramm, Christoph; Altfeld, Marcus; Tiegs, Gisa.
In: J HEPATOL, Vol. 71, No. 4, 10.2019, p. 773-782.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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T1 - Interferon-γ-dependent immune responses contribute to the pathogenesis of sclerosing cholangitis in mice
AU - Ravichandran, Gevitha
AU - Neumann, Katrin
AU - Berkhout, Laura K
AU - Weidemann, Sören
AU - Langeneckert, Annika E
AU - Schwinge, Dorothee
AU - Poch, Tobias
AU - Huber, Samuel
AU - Schiller, Birgit
AU - Hess, Leonard U
AU - Ziegler, Annerose E
AU - Oldhafer, Karl J
AU - Barikbin, Roja
AU - Schramm, Christoph
AU - Altfeld, Marcus
AU - Tiegs, Gisa
N1 - Copyright © 2019 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
PY - 2019/10
Y1 - 2019/10
N2 - 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.
AB - 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.
U2 - 10.1016/j.jhep.2019.05.023
DO - 10.1016/j.jhep.2019.05.023
M3 - SCORING: Journal article
C2 - 31173810
VL - 71
SP - 773
EP - 782
JO - J HEPATOL
JF - J HEPATOL
SN - 0168-8278
IS - 4
ER -