Key Points
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Liver macrophages comprise Kupffer cells — which are self-maintaining, non-migratory tissue-resident phagocytes that originate from yolk sac-derived precursors during embryogenesis — and monocyte-derived macrophages.
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Kupffer cells are essential for hepatic and systemic homeostasis, as they contribute to metabolism, scavenge bacteria and cellular debris, and induce immunological tolerance.
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Following their activation by danger signals, Kupffer cells modulate inflammation and recruit immune cells — including large numbers of monocytes — to the liver.
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Kupffer cells and monocyte-derived macrophages rapidly adapt their phenotypes in response to local signals, which determine their ability to aggravate or cease liver injury.
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Liver macrophages are crucial in the pathogenesis of acute and chronic liver diseases, in which they orchestrate inflammation, fibrosis, angiogenesis and tumour progression, as well as tissue repair and tumour surveillance.
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Evidence from animal models and early clinical trials in humans indicates that targeting pathogenic liver macrophages might be a promising therapeutic approach in acute and chronic liver diseases.
Abstract
Macrophages represent a key cellular component of the liver, and are essential for maintaining tissue homeostasis and ensuring rapid responses to hepatic injury. Our understanding of liver macrophages has been revolutionized by the delineation of heterogeneous subsets of these cells. Kupffer cells are a self-sustaining, liver-resident population of macrophages and can be distinguished from the monocyte-derived macrophages that rapidly accumulate in the injured liver. Specific environmental signals further determine the polarization and function of hepatic macrophages. These cells promote the restoration of tissue integrity following liver injury or infection, but they can also contribute to the progression of liver diseases, including hepatitis, fibrosis and cancer. In this Review, we highlight novel findings regarding the origin, classification and function of hepatic macrophages, and we discuss their divergent roles in the healthy and diseased liver.
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Acknowledgements
This work was supported by the German Research Foundation (DFG; grants Ta434/3-1, Ta434/5-1 and SFB/TRR57) and by the Interdisciplinary Center for Clinical Research (IZKF), Aachen, Germany.
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Work in the laboratory of F.T. has received research funding from Tobira Therapeutics (California, USA), Galapagos (Belgium) and Noxxon (Germany).
Glossary
- Portal triad
-
The anatomical structure within the liver in which branches of the hepatic artery, portal vein and bile ducts align. The portal triad is the typical region of pro-inflammatory and fibrotic responses in liver injury.
- Alarmins
-
Signal molecules released by damaged, diseased or dead cells that activate immune cells.
- Necroptosis
-
A specific variation of programmed necrosis, which is an inflammatory cell death process. Necroptosis is dependent on the activity of receptor-interacting protein kinases.
- Liver decompensation
-
A deterioration of liver function due to a precipitating event such as bleeding or infections. It is typically characterized by clinical symptoms (for example, ascites and hepatic encephalopathy), complications of portal hypertension (for example, variceal bleeding), and single organ or multi-organ failure.
- Hepatic stellate cells
-
Vitamin A-storing, star-shaped cells that have radially extending filaments. These cells are located in the subendothelial space in the liver and can trans-differentiate into extracellular matrix-producing myofibroblasts that promote liver fibrosis.
- Nonalcoholic fatty liver disease
-
(NAFLD). The most common type of liver disease in the world. It is characterized by an excessive accumulation of hepatic fat (steatosis in > 5% of hepatocytes), and is unrelated to alcohol consumption or other secondary causes, but associated with metabolic comorbidities such as obesity and insulin resistance.
- Nonalcoholic steatohepatitis
-
(NASH). The inflammatory stage of nonalcoholic fatty liver disease in which there is a high risk of progressing to cirrhosis or liver cancer. It is characterized by steatosis, hepatocyte ballooning and lobular inflammation, which are observed by liver histology.
- Myeloid-derived suppressor cells
-
(MDSCs). A heterogeneous population of myeloid cells that have potent immune-suppressive properties (for example, they produce anti-inflammatory cytokines, direct T cell suppression and induce the development of regulatory T cells). They arise in conditions of chronic inflammation, infections and tumours.
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Krenkel, O., Tacke, F. Liver macrophages in tissue homeostasis and disease. Nat Rev Immunol 17, 306–321 (2017). https://doi.org/10.1038/nri.2017.11
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DOI: https://doi.org/10.1038/nri.2017.11
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