Key Points
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The liver is a central immunological organ with a high density of myeloid (such as Kupffer cells, neutrophils or macrophages) and lymphoid (such as natural killer cells, T cells or B cells) immune cells
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As antigen-rich blood from the gastrointestinal tract and gut-derived endotoxins pass through the sinusoids, many mechanisms in homeostasis ensure suppression of innate and adaptive immune responses, resulting in tolerance
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In conditions of hepatic diseases, conserved mechanisms such as molecular danger patterns (alarmins), Toll-like receptor signalling or inflammasome activation initiate inflammatory responses, resulting in the chemokine-mediated hepatic infiltration of circulating leukocytes
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Kupffer cells and monocyte-derived macrophages adapt their phenotype to local signals and exert critical functions in perpetuating inflammation and wound healing, but can also mediate resolution of inflammation and fibrosis
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Innate lymphocytes (for example, natural killer and natural killer T cells) are another source of immunoregulatory cytokines in diseased livers and furthermore contribute to eliminating activated myofibroblasts and infected, injured or malignant cells
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The heterogeneous pool of hepatic T cells is activated towards immunity upon injury, resulting in immune-stimulatory cytokine secretion as well as direct cytopathic functions, especially in viral and autoimmune hepatitis
Abstract
The liver is a central immunological organ with a high exposure to circulating antigens and endotoxins from the gut microbiota, particularly enriched for innate immune cells (macrophages, innate lymphoid cells, mucosal-associated invariant T (MAIT) cells). In homeostasis, many mechanisms ensure suppression of immune responses, resulting in tolerance. Tolerance is also relevant for chronic persistence of hepatotropic viruses or allograft acceptance after liver transplantation. The liver can rapidly activate immunity in response to infections or tissue damage. Depending on the underlying liver disease, such as viral hepatitis, cholestasis or NASH, different triggers mediate immune-cell activation. Conserved mechanisms such as molecular danger patterns (alarmins), Toll-like receptor signalling or inflammasome activation initiate inflammatory responses in the liver. The inflammatory activation of hepatic stellate and Kupffer cells results in the chemokine-mediated infiltration of neutrophils, monocytes, natural killer (NK) and natural killer T (NKT) cells. The ultimate outcome of the intrahepatic immune response (for example, fibrosis or resolution) depends on the functional diversity of macrophages and dendritic cells, but also on the balance between pro-inflammatory and anti-inflammatory T-cell populations. As reviewed here, tremendous progress has helped to understand the fine-tuning of immune responses in the liver from homeostasis to disease, indicating promising targets for future therapies in acute and chronic liver diseases.
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Acknowledgements
The authors are supported by the German Research Foundation (DFG Ta434/3-1, SFB/TRR 57) and the Interdisciplinary Center for Clinical Research (IZKF) Aachen.
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Work in the laboratory of F.T. has been funded by Noxxon and Tobira Therapeutics. F.H. declares no competing interests.
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Heymann, F., Tacke, F. Immunology in the liver — from homeostasis to disease. Nat Rev Gastroenterol Hepatol 13, 88–110 (2016). https://doi.org/10.1038/nrgastro.2015.200
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DOI: https://doi.org/10.1038/nrgastro.2015.200
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