24-Norursodeoxycholic acid reshapes immunometabolism in CD8+ T cells and alleviates hepatic inflammation

[摘要] 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 noncholestatic 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 24norursodeoxycholic 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. (C) 2021 The Author(s). Published by Elsevier B.V. on behalf of European Association for the Study of the Liver.

[发布日期] 2021-11-01

[关键词] Primary Sclerosing Cholangitis;Immune-mediated liver disease;bile acid;mass spectrometry;CD8(+) T cells;metabolism;(phospho-) proteome