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SHR Neuro Krebs Kardio Lipid Stoffw Microb

Zhu, C; Boucheron, N; Müller, AC; Májek, P; Claudel, T; Halilbasic, E; Baazim, H; Lercher, A; Viczenczova, C; Hainberger, D; Preglej, T; Sandner, L; Alteneder, M; Gülich, AF; Khan, M; Hamminger, P; Remetic, J; Ohradanova-Repic, A; Schatzlmaier, P; Donner, C; Fuchs, CD; Stojakovic, T; Scharnagl, H; Sakaguchi, S; Weichhart, T; Bergthaler, A; Stockinger, H; Ellmeier, W; Trauner, M.
24-Norursodeoxycholic acid reshapes immunometabolism in CD8+ T cells and alleviates hepatic inflammation.
J Hepatol. 2021; 75(5):1164-1176 Doi: 10.1016/j.jhep.2021.06.036 [OPEN ACCESS]
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Führende Autor*innen der Med Uni Graz
Trauner Michael
Co-Autor*innen der Med Uni Graz
Claudel Thierry
Halilbasic Emina
Scharnagl Hubert
Stojakovic Tatjana
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Abstract:
BACKGROUND & AIMS: 24-Norursodeoxycholic acid (NorUDCA) is a novel therapeutic bile acid used to treat immune-mediated cholestatic liver diseases, such as primary sclerosing cholangitis (PSC), where dysregulated T cells including CD8+ T cells contribute to hepatobiliary immunopathology. We hypothesized that NorUDCA may directly modulate CD8+ T cell function thus contributing to its therapeutic efficacy. METHODS: NorUDCA's immunomodulatory effects were first studied in Mdr2-/- mice, as a cholestatic model of PSC. To differentiate NorUDCA's immunomodulatory effects on CD8+ T cell function from its anticholestatic actions, we also used a non-cholestatic model of hepatic injury induced by an excessive CD8+ T cell immune response upon acute non-cytolytic lymphocytic choriomeningitis virus (LCMV) infection. Studies included molecular and biochemical approaches, flow cytometry and metabolic assays in murine CD8+ T cells in vitro. Mass spectrometry was used to identify potential CD8+ T cell targets modulated by NorUDCA. The signaling effects of NorUDCA observed in murine cells were validated in circulating T cells from patients with PSC. RESULTS: NorUDCA demonstrated immunomodulatory effects by reducing hepatic innate and adaptive immune cells, including CD8+ T cells in the Mdr2-/- model. In the non-cholestatic model of CD8+ T cell-driven immunopathology induced by acute LCMV infection, NorUDCA ameliorated hepatic injury and systemic inflammation. Mechanistically, NorUDCA demonstrated strong immunomodulatory efficacy in CD8+ T cells affecting lymphoblastogenesis, expansion, glycolysis and mTORC1 signaling. Mass spectrometry identified that NorUDCA regulates CD8+ T cells by targeting mTORC1. NorUDCA's impact on mTORC1 signaling was further confirmed in circulating PSC CD8+ T cells. CONCLUSIONS: NorUDCA has a direct modulatory impact on CD8+ T cells and attenuates excessive CD8+ T cell-driven hepatic immunopathology. These findings are relevant for treatment of immune-mediated liver diseases such as PSC. LAY SUMMARY: Elucidating the mechanisms by which 24-norursodeoxycholic acid (NorUDCA) works for the treatment of immune-mediated liver diseases, such as primary sclerosing cholangitis, is of considerable clinical interest. Herein, we uncovered an unrecognized property of NorUDCA in the immunometabolic regulation of CD8+ T cells, which has therapeutic relevance for immune-mediated liver diseases, including PSC.

Find related publications in this database (Keywords)
Primary Sclerosing Cholangitis
Immune-mediated liver disease
bile acid
mass spectrometry
CD8(+) T cells
metabolism
(phospho-) proteome
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