Research paperDynamic plasticity of macrophage functions in diseased liver
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.
References (101)
Targeting hepatic macrophages to treat liver diseases
J. Hepatol.
(2017)Combination of mass cytometry and imaging analysis reveals origin, location, and functional repopulation of liver myeloid cells in mice
Gastroenterology
(2016)- et al.
Scavenger receptors on liver Kupffer cells mediate the in vivo uptake of oxidatively damaged red blood cells in mice
Blood
(2000) - et al.
Measurement of bacterial capture and phagosome maturation of Kupffer cells by intravital microscopy
Methods
(2017) - et al.
Most tissue-resident macrophages except microglia are derived from fetal hematopoietic stem cells
Immunity
(2015) C-Myb(+) erythro-myeloid progenitor-derived fetal monocytes give rise to adult tissue-resident macrophages
Immunity
(2015)Tissue-resident macrophage enhancer landscapes are shaped by the local microenvironment
Cell
(2014)- et al.
Tissue-specific signals control reversible program of localization and functional polarization of macrophages
Cell
(2014) Bone marrow-derived and resident liver macrophages display unique transcriptomic signatures but similar biological functions
J. Hepatol.
(2016)Role of hepatic resident and infiltrating macrophages in liver repair after acute injury
Biochem. Pharmacol.
(2013)
Role of CCR2 in macrophage migration into the liver during acetaminophen-induced hepatotoxicity in the mouse
Hepatology
Liver ischemia and reperfusion injury: new insights into mechanisms of innate-adaptive immune-mediated tissue inflammation
Am. J. Transplant.
Arginase 2 deficiency results in spontaneous steatohepatitis: a novel link between innate immune activation and hepatic de novo lipogenesis
J. Hepatol.
Toll-like receptor-4 signaling and Kupffer cells play pivotal roles in the pathogenesis of non-alcoholic steatohepatitis
J. Hepatol.
CXC chemokine receptor 3 promotes steatohepatitis in mice through mediating inflammatory cytokines, macrophages and autophagy
J. Hepatol.
CD44 is a key player in non-alcoholic steatohepatitis
J. Hepatol.
Clinical evidence for the regression of liver fibrosis
J. Hepatol.
Activated stellate cells express the TRAIL receptor-2/death receptor-5 and undergo TRAIL-mediated apoptosis
Hepatology
Caspase 9-dependent killing of hepatic stellate cells by activated Kupffer cells
Gastroenterology
Cytotherapy with M1-polarized macrophages ameliorates liver fibrosis by modulating immune microenvironment in mice
J. Hepatol.
Phenotypic and functional characterization of macrophages with therapeutic potential generated from human cirrhotic monocytes in a cohort study
Cytotherapy
Hallmarks of cancer: the next generation
Cell
High tumor-infiltrating macrophage density predicts poor prognosis in patients with primary hepatocellular carcinoma after resection
Hum. Pathol.
Distinct patterns and prognostic values of tumor-infiltrating macrophages in hepatocellular carcinoma and gastric cancer
J. Transl. Med.
A new population of myeloid-derived suppressor cells in hepatocellular carcinoma patients induces CD4(+)CD25(+)Foxp3(+) T cells
Gastroenterology
Tissue-resident versus monocyte-derived macrophages in the tumor microenvironment
BBA
Distinct functions of senescence-associated immune responses in liver tumor surveillance and tumor progression
Cancer Cell
Conditional probability of long-term survival after resection of hilar cholangiocarcinoma
HPB (Oxford)
Elevated levels of circulating osteopontin are associated with a poor survival after resection of cholangiocarcinoma
J. Hepatol.
Immunology in the liver – from homeostasis to disease
Nat. Rev. Gastroenterol. Hepatol.
Liver macrophages in tissue homeostasis and disease
Nat. Rev. Immunol.
Bone marrow-derived monocytes give rise to self-renewing and fully differentiated Kupffer cells
Nat. Commun.
Chemokine (C-C motif) receptor 2-positive monocytes aggravate the early phase of acetaminophen-induced acute liver injury
Hepatology
Liver fibrosis: from pathogenesis to novel therapies
Dig. Dis.
The origin and kinetics of mononuclear phagocytes
J. Exp. Med.
Lineage-specific enhancers activate self-renewal genes in macrophages and embryonic stem cells
Science
Tissue-resident macrophages originate from yolk-sac-derived erythro-myeloid progenitors
Nature
Does niche competition determine the origin of tissue-resident macrophages?
Nat. Rev. Immunol.
Differential Ly-6C expression identifies the recruited macrophage phenotype, which orchestrates the regression of murine liver fibrosis
Proc. Natl. Acad. Sci. U.S.A.
Single-cell RNA-seq reveals new types of human blood dendritic cells, monocytes, and progenitors
Science
Single-cell spatial reconstruction reveals global division of labour in the mammalian liver
Nature
Molecular imaging with Kupffer cell-targeting nanobodies for diagnosis and prognosis in mouse models of liver pathogenesis
Mol. Imaging Biol.
Barrier-tissue macrophages: functional adaptation to environmental challenges
Nat. Med.
Acute liver failure
N. Engl. J. Med.
Understanding paracetamol-induced liver failure
Intensive Care Med.
Immune mechanisms in acetaminophen-induced acute liver failure
Hepatobiliary Surg. Nutr.
Identification and characterization of infiltrating macrophages in acetaminophen-induced liver injury
J. Leukoc. Biol.
Infiltrating monocyte-derived macrophages and resident kupffer cells display different ontogeny and functions in acute liver injury
J. Immunol.
Source and characterization of hepatic macrophages in acetaminophen-induced acute liver failure in humans
Hepatology
Ly6Chi monocytes and their macrophage descendants regulate neutrophil function and clearance in acetaminophen-induced liver injury
Front. Immunol.
Cited by (44)
Single-cell atlas of the liver myeloid compartment before and after cure of chronic viral hepatitis
2024, Journal of HepatologySelective suppression of M1 macrophages is involved in zinc inhibition of liver fibrosis in mice
2021, Journal of Nutritional BiochemistryCitation Excerpt :These macrophages are derived from residential pool as well as infiltration of macrophages in the initiation stage of fibrogenesis [15,18,23]. Monocyte-derived macrophages purified from animals with liver fibrosis were also shown to contribute to activation of HSCs [30,31], although monocytes from patients with chronic liver disease can directly activate HSCs [32]. Considering the critical role of macrophages in the activation of HSCs, the suppression of macrophages by zinc supplementation observed in this study would be an important event in the inhibition of liver fibrosis.
Advances in the research of nanodrug delivery system for targeted treatment of liver fibrosis
2021, Biomedicine and PharmacotherapyCitation Excerpt :Kupffer cells, the unique resident macrophages of the liver, are known to play a pivotal role in eliminating exogenous foreign bodies and apoptotic cells and maintaining the stability of the liver environment. These cells can also regulate liver fibrosis either positively or negatively by changing cell phenotype before and after liver injury [69,70]. Therefore, they can be used as potential target cells for the treatment of liver fibrosis.