Liver infiltrating T cells regulate bile acid metabolism in experimental cholangitis.

Authors:
Fabian Glaser, Clara John, Bastian Engel, Benedikt Höh, Sören Weidemann, Jan Dieckhoff, Stephanie Stein, Nathalie Becker, Christian Casar, Fenja Amrei Schuran, Björn Wieschendorf, Max Preti, Friederike Jessen, Andre Franke, Antonella Carambia, Ansgar W Lohse, Harald Ittrich, Johannes Herkel, Joerg Heeren, Christoph Schramm, Dorothee Schwinge
Year of publication:
2019
Volume:
-
Issue:
-
Issn:
0168-8278
Journal title abbreviated:
J HEPATOL
Journal title long:
Journal of hepatology : the journal of the European Association for the Study of the Liver
Impact factor:
10.590
Abstract:
BACKGROUND AND AIMS:T cells are central mediators of liver inflammation and represent potential treatment targets in cholestatic liver disease. Whereas emerging evidence shows that bile acids (BA) affect T cell function, the role of T cells for the regulation of BA metabolism is unknown. In order to understand this interplay, we investigated the influence of T cells on BA metabolism in a novel mouse model of cholangitis. METHODS:Mdr2-/- mice were crossed with transgenic K14-OVAp mice, which express an MHC class I restricted ovalbumin peptide on biliary epithelial cells (Mdr2-/-xK14-OVAp). T cell mediated cholangitis was induced by the adoptive transfer of antigen specific CD8+ T cells. BA levels were quantified using a targeted liquid chromatography-mass spectrometry-based approach. RESULTS:T cell-induced cholangitis resulted in reduced levels of unconjugated BA (uBA) in the liver and significantly increased serum and hepatic levels of conjugated BA (cBA). Genes responsible for BA synthesis and uptake were downregulated and expression of the bile salt export pump was increased. The transferred antigen-specific CD8+ T cells alone were able to induce these changes, as demonstrated using Mdr2-/-xK14-OVAp recipient mice on the RAG1-/- background. Mechanistically, we showed by depletion experiments that alterations in BA metabolism were partly mediated by the proinflammatory cytokines TNF and IFNgamma in a FXR-dependent manner, a process that in vitro required cell contact between T cells and hepatocytes. CONCLUSION:Whereas it is known that BA metabolism is dysregulated in sepsis and related conditions, we here show that T cells are able to control synthesis and metabolism of BA, a process which depends on TNF and IFNgamma. Understanding the effect of lymphocytes on BA metabolism will help to design combined treatment strategies for cholestatic liver diseases. LAY SUMMARY:Dysregulation of bile acid metabolism as well as of T cells could contribute to the development of cholangiopathies. Before targeting T cells for the treatment of cholangiopathies it should be investigated whether these cells exert potentially protective effects on bile acid metabolism. We here demonstrate that T cell induced cholangitis resulted in decreased levels of harmful unconjugated bile acids. T cells were able to directly control synthesis and metabolism of BA, a process which was dependent on proinflammatory cytokines TNF and IFNgamma. Understanding the effect of lymphocytes on BA metabolism will help to design combined treatment strategies for cholestatic liver diseases.