Elsevier

Cellular Immunology

Volume 330, August 2018, Pages 175-182
Cellular Immunology

Research paper
Dynamic plasticity of macrophage functions in diseased liver

https://doi.org/10.1016/j.cellimm.2017.12.007Get rights and content

Highlights

  • Hepatic macrophage subsets have critical functions in homeostasis and inflammation.

  • They adapt to signals and can exert bidirectional roles in multiple liver diseases.

  • Liver macrophages modulate acute injury, steatohepatitis, fibrosis and cancer.

  • Hepatic macrophages are a promising target for novel therapeutic interventions.

  • Thorough understanding of their plastic and complex network is mandatory.

Abstract

Liver macrophages attract increasing interest due to their crucial roles in homeostasis and hepatic diseases. Recent findings in mice and man suggest a remarkable phenotypic and functional diversity of liver macrophages. Kupffer cells, the subset of tissue resident macrophages with sentinel functions in liver, mainly arise from embryogenic precursors, whereas in injury, liver tissue is engrafted by monocyte-derived macrophages. Both principal macrophage populations respond to local or systemic signals and have substantial effects on reduction as well as aggravation of hepatic diseases. Despite contrasting functions of heterogeneous macrophage subsets in disease progression and regression, they may provide promising targets for novel therapeutic interventions in hepatology. Areas of intense research include their multifaceted roles in metabolic diseases (non-alcoholic steatohepatitis, NASH), fibrosis or liver cancer (hepatocellular or cholangiocellular carcinoma, HCC or CCA). We discuss recent findings on the origin, diversity and functional plasticity of liver macrophages in homeostasis and hepatic disease conditions.

Introduction

The liver is the largest parenchymal organ with many vital functions such as detoxification, glycogen storage, metabolism or protein synthesis. In addition, the liver is enriched with manifold tissue-resident and patrolling immune cells that partake in sustaining homeostasis and responding to injury. The role of the immune system in the pathogenesis of liver diseases is a subject of intense research activities [1]. Innate immune cells are particularly relevant in the liver, especially hepatic macrophages. They are located at the luminal side of the sinusoidal endothelium, where they are exposed to antigens, microbial products or proteins from the gastrointestinal tract (drained via the portal vein) as well as in close communication with patrolling immune cells and parenchymal (i.e. hepatocytes and cholangiocytes) or non-parenchymal (e.g., endothelium, hepatic stellate cells) liver cells. Thereby, liver macrophages ensure both, microenvironmental and whole body homeostasis.

Hepatic macrophages consist of distinct subsets with diverse functions and play a central role in the development of multiple liver diseases, including hepatitis, cirrhosis and cancer [2]. In principle, macrophages harbor enormous potential in cell specific drug targeting [3], but they exert bidirectional roles in many liver diseases. Due to their plasticity and complexity, an accurate understanding regarding their disease related functions is mandatory. Macrophages are abundant in liver and can be generally subdivided into two distinct subclasses. Kupffer cells, non-migratory tissue resident macrophages in liver, are located in the sinusoids, and maintain homeostasis (e.g., bacterial clearance, elimination of damaged erythrocytes) [4], [5], [6]. A second type of liver macrophages arises from circulating blood monocytes or myeloid precursors, shows migratory properties and engrafts liver tissue under inflammatory conditions or after Kupffer cell depletion [7], [8]. The liver tissue is continuously exposed to blood from the intestine, drained by the portal vein, thus macrophages are important gatekeepers for initiating or suppressing immune responses (Fig. 1). Progression of liver diseases is a prime example to study the effects caused by sustained inflammation leading to a scarring process and finally cancer [9]. Sophisticated mouse models revealed fundamental mechanisms orchestrating liver diseases, whereas further translational research is indispensable in order to transfer the results to humans.

Section snippets

Heterogeneity of liver phagocytes in development and during homeostasis

Macrophages are myeloid cells and belong to the mononuclear phagocyte system [10]. Differentiated macrophages have the ability of self-maintenance due to a downregulation of the transcription factors MafB/c-Maf and activation of a gene network responsible for self-renewal [11]. During the last years, a change of paradigm in macrophage development started, when several findings pointed out that most tissue-resident macrophages are derived from embryonic precursors. Using mouse fate mapping

Macrophages in acute liver injury

Acute liver failure is a life-threatening condition with a rapid loss of liver function, resulting in accumulation of toxic metabolites and disturbed blood coagulation, which can progress to multi-organ failure. Despite modern critical care management and liver transplantation as ultima ratio, acute liver failure is still associated with high mortality [24]. In developed western countries acute liver failure is mostly related to drug-induced liver injury rather than to acute viral hepatitis,

Macrophages in fatty liver disease

Due to the precipitous increase of associated conditions like obesity, dyslipidemia and type 2 diabetes, nonalcoholic fatty liver disease (NAFLD) became the most common liver disease in western countries, with an immense clinical and economic burden [40], [41]. NAFLD can progress from simple (and benign) steatosis (i.e. fatty liver) to nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis and even hepatocellular carcinoma (HCC) [42], [43]. Dysregulation of lipid metabolism (including changes

Macrophages in fibrosis and cirrhosis

Sustained liver damage engenders fibrosis and cirrhosis with life-threatening complications due to insufficient organ function and portal hypertension. Until some years ago, it was assumed that this scarring process is irreversible. However, this dogma no longer applies, since recent studies have highlighted that liver fibrosis can be reverted; alongside with others, macrophages are mediators of both fibrosis progression and regression [9], [61]. Hepatic stellate cells (HSC) are known to be the

Macrophages in liver cancer

Liver tissue is not only origin of primary liver cancers as hepatocellular carcinoma or cholangiocarcinoma, but more often it is the target organ of distant metastasis. Avoiding immune destruction as well as tumor-promoting inflammation are important components regarding the hallmarks of cancer [76]. Therefore, it is likely that we will see a considerable rise in immune modulatory therapeutics in addition to conventional and/or new generations of chemotherapeutics as an indispensable component

Conclusions

Hepatic macrophages are a heterogeneous cell population and key players in homeostasis and injury. Animal models elucidated pivotal and even opposing functions in the pathogenesis of multiple liver diseases. Liver macrophages are certainly a promising target for novel therapeutic interventions of acute liver injury, hepatic manifestation of metabolic diseases, fibrosis or even cancer. Modulations of monocyte/macrophage recruitment, macrophage polarization or cytokine inhibition are interesting

Acknowledgments

This work was supported by the German Research Foundation (DFG; Ta434/3-1, Ta434/5-1, and SFB/TRR57) and by the Interdisciplinary Center for Clinical Research (IZKF) Aachen.

Conflict of Interest

Work in the lab of F.T. has received research funding by Tobira Therapeutics, Galapagos and Noxxon.

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