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Immunometabolism of pro-repair cells.

ABSTRACT: Immune cell populations determine the balance between ongoing damage and repair following tissue injury. Cells responding to a tissue-damaged environment have significant bioenergetic and biosynthetic needs. In addition to supporting these needs, metabolic pathways govern the function of pro-repair immune cells, including regulatory T cells and tissue macrophages. In this Review, we explore how specific features of the tissue-damaged environment such as hypoxia, oxidative stress, and nutrient depletion serve as metabolic cues to promote or impair the reparative functions of immune cell populations. Hypoxia, mitochondrial DNA stress, and altered redox balance each contribute to mechanisms regulating the response to tissue damage. For example, hypoxia induces changes in regulatory T cell and macrophage metabolic profiles, including generation of 2-hydroxyglutarate, which inhibits demethylase reactions to modulate cell fate and function. Reactive oxygen species abundant in oxidative environments cause damage to mitochondrial DNA, initiating signaling pathways that likewise control pro-repair cell function. Nutrient depletion following tissue damage also affects pro-repair cell function through metabolic signaling pathways, specifically those sensitive to the redox state of the cell. The study of immunometabolism as an immediate sensor and regulator of the tissue-damaged environment provides opportunities to consider mechanisms that facilitate healthy repair of tissue injury.

SUBMITTER: Singer BD

PROVIDER: S-EPMC6597201 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Immunometabolism of pro-repair cells.

Singer Benjamin D BD Chandel Navdeep S NS

The Journal of clinical investigation 20190513 7

Immune cell populations determine the balance between ongoing damage and repair following tissue injury. Cells responding to a tissue-damaged environment have significant bioenergetic and biosynthetic needs. In addition to supporting these needs, metabolic pathways govern the function of pro-repair immune cells, including regulatory T cells and tissue macrophages. In this Review, we explore how specific features of the tissue-damaged environment such as hypoxia, oxidative stress, and nutrient de ...[more]

PMID: 31081802

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Project description:Background & aims24-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.MethodsNorUDCA'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.ResultsNorUDCA 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.ConclusionsNorUDCA 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 summaryElucidating 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.

Dataset Information

Immunometabolism of pro-repair cells.

Publications

Immunometabolism of pro-repair cells.

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