Hepatic Macrophage Populations Research Articles

Survivin inhibition ameliorates liver fibrosis by inducing hepatic stellate cell senescence and depleting hepatic macrophage population.

Persistent activation of hepatic stellate cells (HSCs) in the injured liver leads to the progression of liver injury from fibrosis to detrimental cirrhosis. In a previous study, we have shown that survivin protein is upregulated during the early activation of HSCs, which triggers the onset of liver fibrosis. However, the therapeutic potential of targeting survivin in a fully established fibrotic liver needs to be investigated. In this study, we chemically induced hepatic fibrosis in mice using carbon tetrachloride (CCl4) for 6weeks, which was followed by treatment with a survivin suppressant (YM155). We also evaluated survivin expression in fibrotic human liver tissues, primary HSCs, and HSC cell line by histological analysis. αSMA+ HSCs in human and mice fibrotic liver tissues showed enhanced survivin expression, whereas the hepatocytes and quiescent (qHSCs) displayed minimal expression. Alternatively, activated M2 macrophage subtype induced survivin expression in HSCs through the TGF-β-TGF-β receptor-I/II signaling. Inhibition of survivin in HSCs promoted cell cycle arrest and senescence, which eventually suppressed their activation. In vivo, YM155 treatment increased the expression of cell senescence makers in HSCs around fibrotic septa such as p53, p21, and β-galactosidase. YM155 treatment in vivo also reduced the hepatic macrophage population and inflammatory cytokine expression in the liver. In conclusion, downregulation of survivin in the fibrotic liver decreases HSC activation by inducing cellular senescence and modulating macrophage cytokine expression that collectively ameliorates liver fibrosis.

Ontogeny, functions and reprogramming of Kupffer cells upon infectious disease.

The liver is a vital metabolic organ that also performs important immune-regulatory functions. In the context of infections, the liver represents a target site for various pathogens, while also having an outstanding capacity to filter the blood from pathogens and to contain infections. Pathogen scavenging by the liver is primarily performed by its large and heterogeneous macrophage population. The major liver-resident macrophage population is located within the hepatic microcirculation and is known as Kupffer cells (KCs). Although other minor macrophages reside in the liver as well, KCs remain the best characterized and are the best well-known hepatic macrophage population to be functionally involved in the clearance of infections. The response of KCs to pathogenic insults often governs the overall severity and outcome of infections on the host. Moreover, infections also impart long-lasting, and rarely studied changes to the KC pool. In this review, we discuss current knowledge on the biology and the various roles of liver macrophages during infections. In addition, we reflect on the potential of infection history to imprint long-lasting effects on macrophages, in particular liver macrophages.

Distinct spatial distribution and roles of Kupffer cells and monocyte-derived macrophages in mouse acute liver injury.

Macrophages are key regulators of inflammation and repair, but their heterogeneity and multiple roles in the liver are not fully understood. We aimed herein to map the intrahepatic macrophage populations and their function(s) during acute liver injury. We used flow cytometry, gene expression analysis, multiplex-immunofluorescence, 3D-reconstruction, and spatial image analysis to characterize the intrahepatic immune landscape in mice post-CCl4-induced acute liver injury during three distinct phases: necroinflammation, and early and late repair. We observed hepatocellular necrosis and a reduction in liver resident lymphocytes during necroinflammation accompanied by the infiltration of circulating myeloid cells and upregulation of inflammatory cytokines. These parameters returned to baseline levels during the repair phase while pro-repair chemokines were upregulated. We identified resident CLEC4F+ Kupffer cells (KCs) and infiltrating IBA1+CLEC4F- monocyte-derived macrophages (MoMFs) as the main hepatic macrophage populations during this response to injury. While occupying most of the necrotic area, KCs and MoMFs exhibited distinctive kinetics, distribution and morphology at the site of injury. The necroinflammation phase was characterized by low levels of KCs and a remarkable invasion of MoMFs suggesting their potential role in phagoctosing necrotic hepatocytes, while opposite kinetics/distribution were observed during repair. During the early repair phase, yolksac - derived KCs were restored, whereas MoMFs diminished gradually then dissipated during late repair. MoMFs interacted with hepatic stellate cells during the necroinflammatory and early repair phases, potentially modulating their activation state and influencing their fibrogenic and pro-repair functions that are critical for wound healing. Altogether, our study reveals novel and distinct spatial and temporal distribution of KCs and MoMFs and provides insights into their complementary roles during acute liver injury.

An Eye on Kupffer Cells: Development, Phenotype and the Macrophage Niche.

Macrophages are key participants in the maintenance of tissue homeostasis under normal and pathological conditions, and implement a rich diversity of functions. The largest population of resident tissue macrophages is found in the liver. Hepatic macrophages, termed Kupffer cells, are involved in the regulation of multiple liver functionalities. Specific differentiation profiles and functional activities of tissue macrophages have been attributed to the shaping role of the so-called tissue niche microenvironments. The fundamental macrophage niche concept was lately shaken by a flood of new data, leading to a revision and substantial update of the concept, which constitutes the main focus of this review. The macrophage community discusses contemporary evidence on the developmental origins of resident macrophages, notably Kupffer cells and the issues of heterogeneity of the hepatic macrophage populations, as well as the roles of proliferation, cell death and migration processes in the maintenance of macrophage populations of the liver. Special consideration is given to interactions of Kupffer cells with other local cell lineages, including Ito cells, sinusoidal endothelium and hepatocytes, which participate in the maintenance of their phenotypical and functional identity.

Location, location, location - spatial insight into hepatic macrophage populations.

Location, location, location - spatial insight into hepatic macrophage populations.

Single Cell RNA Sequencing in NASH.

Single cell RNA sequencing (scRNA-seq) allows to uncover cellular heterogeneity and the identification of novel subpopulations. In non-alcoholic steatohepatitis (NASH), scRNA-seq is particularly powerful to understand non-parenchymal cell heterogeneity in the liver, e.g. for inflammatory cells. Myeloid immune cells, particularly macrophages, play a critical role in response of the innate immune system and significantly contribute to the progression of fatty liver disease. Due to their high heterogeneity and complex phenotypes, their functional role in health and disease is difficult to analyze. Here, we describe the isolation and analysis of myeloid cell populations from mouse liver using microdroplet-based scRNA-seq. This approach allows the identification and characterization of different hepatic cell types, exemplified here by hepatic macrophage populations, as well as analyses of differentially expressed genes between samples (e.g., cells from healthy or NASH livers).

Metallothioneins alter macrophage phenotype and represent novel therapeutic targets for acetaminophen-induced liver injury.

Acetaminophen (APAP) intoxication is the foremost cause of drug-induced liver failure in developed countries. The only pharmacologic treatment option, N-acetylcysteine (NAC), is not effective for patients who are admitted too late and/or who have excessive liver damage, emphasizing the need for alternative treatment options. APAP intoxication results in hepatocyte death and release of danger signals, which further contribute to liver injury, in part by hepatic monocyte/macrophage infiltration and activation. Metallothionein (MT) 1 and 2 have important danger signaling functions and might represent novel therapeutic targets in APAP overdose. Therefore, we evaluated hepatic MT expression and the effect of anti-MT antibodies on the transcriptional profile of the hepatic macrophage population and liver injury following APAP overdose in mice. Hepatic MT expression was significantly induced in APAP-intoxicated mice and abundantly present in human livers. APAP intoxication in mice resulted in increased serum transaminase levels, extended necrotic regions on liver histology and induced expression of proinflammatory markers, which was significantly less pronounced in mice treated with anti-MT antibodies. Anti-MT antibody therapy attenuated proinflammatory macrophage polarization, as demonstrated by RNA sequencing analyses of isolated liver macrophages and in LPS-stimulated bone marrow-derived macrophages. Importantly, NAC and anti-MT antibodies were equally effective whereas administration of anti-MT antibody in combination with NAC exceeded the efficiency of both monotherapies in APAP-induced liver injury (AILI). We conclude that the neutralization of secreted MTs using a monoclonal antibody is a novel therapeutic strategy as mono- or add-on therapy for AILI. In addition, we provide evidence suggesting that MTs in the extracellular environment are involved in macrophage polarization.

Characterization of macrophages in the liver of total body irradiated mice

Abstract Two hepatic macrophage (MΦ) populations have been described in the inflamed liver: F4/80+CD11b+ cells and F4/80+CD68+ cells. In normal conditions, hepatic F4/80+CD11b+ cells are involved in host antibacterial resistance. However, these cells in total body irradiated mice (TBI mice) are unfunctional for the elimination of bacteria translocated from intestinal tracts. In this study, the properties of hepatic MΦ populations in TBI mice were characterized. Normal mice and mice 7 days after exposure to 4 Gy of X-rays were infected i.v. with 107 CFU/mouse of Enterococcus faecalis (E. faecalis). Three day after infection, F4/80+CD11b+ cells and F4/80+CD68+ cells isolated from the liver of these mice were cultured for 24 hrs, and culture fluids were assayed for IL-12, IL-10 and CCL1 by ELISA. NSG mice were inoculated i.v. with these MΦ preparations (2 × 105 cells/mouse), then infected i.v. with 5 × 104 CFU/mouse of E. faecalis. In the results, all TBI mice died within 2 weeks, while all normal mice survived. IL-12 was produced by F4/80+CD11b+ cells from normal mice, but not by both MΦ preparations from TBI mice. IL-10 was produced by F4/80+CD68+ cells from TBI mice (529.9 ± 272.6 pg/ml) and normal mice (445.8 ± 147.7 pg/ml). Large amounts of IL-10 (912.1 ± 103.7 pg/ml) was produced by F4/80+CD11b+ cells from TBI mice, and these cells produced CCL1 (327.5 ± 9.1 pg/ml), while other MΦ preparations did not. NSG mice inoculated with F4/80+CD11b+ cells from normal mice were resistant to infection; however, NSG mice inoculated with F4/80+CD11b+ cells from TBI mice did not. These results indicate hepatic F4/80+CD11b+ cells are polarized to M2bMΦ in response to total body irradiation, and these MΦ are involved in the decreased host antibacterial resistance in TBI mice.

Regulation of macrophage activation in the liver after acute injury: Role of the fibrinolytic system.

The liver functions, in part, to prevent exposure of the body to potentially harmful substances ingested in the diet. While it is highly efficient at accomplishing this, it is frequently prone to liver injury due to the biotransformation of xenobiotics into toxic metabolites. To counter this injury, the liver has evolved a unique capacity to rapidly and efficiently repair itself. Successful resolution of acute liver injury relies on hepatic macrophage populations that orchestrate the reparative response. After injury, Kupffer cells, the resident macrophages of the liver, become activated and secrete proinflammatory cytokines. These cytokines recruit other immune cells, including monocyte-derived macrophages, to the liver where they contribute to the repair process. Monocyte-derived macrophages traffic into the necrotic foci where they rapidly phagocytose dead cell debris. Simultaneous with this process, these cells change phenotype from a proinflammatory macrophage to a pro-restorative macrophage that produce pro-mitogenic growth factors and anti-inflammatory cytokines. Ultimately this process triggers resolution of inflammation, and along with proliferation of other hepatic cells, restores the liver architecture and function. While the mechanisms regulating specific macrophage functions during repair remain to be elucidated, recent studies indicate a key role for the fibrinolytic system in coordinating macrophage function during repair. In this review, we will highlight the function and role of hepatic macrophages in repair after acute liver injury, and will discuss the role of the fibrinolytic enzyme, plasmin, in regulation of these various processes.

Myeloid-specific IRE1alpha deletion reduces tumour development in a diabetic, non-alcoholic steatohepatitis-induced hepatocellular carcinoma mouse model

Background and aimsObesity, diabetes and associated non-alcoholic steatohepatitis (NASH) are rising risk factors for hepatocellular carcinoma (HCC). Macrophages are important immune cells involved in inflammation and tumour development. Macrophage inositol-requiring enzyme 1 alpha (IRE1α), an ER-stress protein, has been shown to be involved in macrophage cytokine production, and myeloid-specific IRE1α knock-out (myeloid IRE1α-KO) mice showed reduced weight gain during high-fat diet feeding. However, the effect of myeloid IRE1α on NASH and subsequent HCC development has not been examined. Here, we characterized the transcriptional profile of the hepatic macrophage population in a diabetes-NASH-HCC mouse model, and investigated the effect of myeloid-specific IRE1α deletion on the phenotype of hepatic macrophage subsets and experimental NASH-HCC development. MethodsMice with non-functional myeloid IRE1α were created by crossing Ire1a floxed mice with Lysm-Cre mice. Two-day old myeloid IRE1α-KO and wild type (WT) mice were subcutaneously injected with streptozotocin (STZ), and male mice were fed a high-fat, -sucrose, -cholesterol diet (Western diet, WD) from the age of 4 weeks until 21 weeks. Control myeloid IRE1α-KO and WT mice received a PBS injection and were fed a matched control diet. These mice were evaluated for obesity, diabetes, NASH and HCC. The hepatic macrophage population was evaluated by flow cytometry and RNA sequencing on FACS-isolated macrophage subsets. ResultsSTZ-injection and WD feeding resulted in an impaired glucose tolerance, advanced NASH with fibrosis, and HCC development. Myeloid IRE1α-KO STZ mice showed lower fasting glucose levels at the start of WD feeding, and an improved glucose tolerance and attenuated HCC development after 17 weeks of WD feeding despite a similar degree of liver steatosis and inflammation compared to WT mice. Transcriptomic analysis of WT liver Kupffer cells, macrophages and monocytes revealed phenotypical changes in those cell subsets during NASH-HCC development. Isolated liver Kupffer cells and macrophages from mice with a myeloid IRE1α deletion showed downregulated pathways involved in immune system activation and metabolic pathways (only in Kupffer cells), whereas pathways involved in cell division and metabolism were upregulated in monocytes. These transcriptional differences were attenuated during NASH-HCC development. ConclusionOur results show that myeloid-specific IRE1α deletion results in an altered transcriptional profile of hepatic macrophages and dampens diabetes-induced NASH-HCC development, possibly by attenuated diabetes induction.

Targeting of Hepatic Macrophages by Therapeutic Nanoparticles.

Hepatic macrophage populations include different types of cells with plastic properties that can differentiate into diverse phenotypes to modulate their properties in response to different stimuli. They often regulate the activity of other cells and play an important role in many hepatic diseases. In response to those pathological situations, they are activated, releasing cytokines and chemokines; they may attract circulating monocytes and exert functions that can aggravate the symptoms or drive reparation processes. As a result, liver macrophages are potential therapeutic targets that can be oriented toward a variety of aims, with emergent nanotechnology platforms potentially offering new perspectives for macrophage vectorization. Macrophages play an essential role in the final destination of nanoparticles (NPs) in the organism, as they are involved in their uptake and trafficking in vivo. Different types of delivery nanosystems for macrophage recognition and targeting, such as liposomes, solid-lipid, polymeric, or metallic nanoparticles, have been developed. Passive targeting promotes the accumulation of the NPs in the liver due to their anatomical and physiological features. This process is modulated by NP characteristics such as size, charge, and surface modifications. Active targeting approaches with specific ligands may also be used to reach liver macrophages. In order to design new systems, the NP recognition mechanism of macrophages must be understood, taking into account that variations in local microenvironment may change the phenotype of macrophages in a way that will affect the uptake and toxicity of NPs. This kind of information may be applied to diseases where macrophages play a pathogenic role, such as metabolic disorders, infections, or cancer. The kinetics of nanoparticles strongly affects their therapeutic efficacy when administered in vivo. Release kinetics could predict the behavior of nanosystems targeting macrophages and be applied to improve their characteristics. PBPK models have been developed to characterize nanoparticle biodistribution in organs of the reticuloendothelial system (RES) such as liver or spleen. Another controversial issue is the possible toxicity of non-degradable nanoparticles, which in many cases accumulate in high percentages in macrophage clearance organs such as the liver, spleen, and kidney.

Dietary Lipids Differentially Shape Nonalcoholic Steatohepatitis Progression and the Transcriptome of Kupffer Cells and Infiltrating Macrophages.

A crucial component of nonalcoholic fatty liver disease (NAFLD) pathogenesis is lipid stress, which may contribute to hepatic inflammation and activation of innate immunity in the liver. However, little is known regarding how dietary lipids, including fat and cholesterol, may facilitate innate immune activation in vivo. We hypothesized that dietary fat and cholesterol drive NAFLD progression to steatohepatitis and hepatic fibrosis by altering the transcription and phenotype of hepatic macrophages. This hypothesis was tested by using RNA-sequencing methods to characterize and analyze sort-purified hepatic macrophage populations that were isolated from mice fed diets with varying amounts of fat and cholesterol. The addition of cholesterol to a high-fat diet triggered hepatic pathology reminiscent of advanced nonalcoholic steatohepatitis (NASH) in humans characterized by signs of cholesterol dysregulation, generation of oxidized low-density lipoprotein, increased recruitment of hepatic macrophages, and significant fibrosis. RNA-sequencing analyses of hepatic macrophages in this model revealed that dietary cholesterol induced a tissue repair and regeneration phenotype in Kupffer cells (KCs) and recruited infiltrating macrophages to a greater degree than fat. Furthermore, comparison of diseased KCs and infiltrating macrophages revealed that these two macrophage subsets are transcriptionally diverse. Finally, direct stimulation of murine and human macrophages with oxidized low-density lipoprotein recapitulated some of the transcriptional changes observed in the RNA-sequencing study. These findings indicate that fat and cholesterol synergize to alter macrophage phenotype, and they also challenge the dogma that KCs are purely proinflammatory in NASH. Conclusion: This comprehensive view of macrophage populations in NASH indicates mechanisms by which cholesterol contributes to NASH progression and identifies potential therapeutic targets for this common disease.

Macrophages in obesity and non-alcoholic fatty liver disease: Crosstalk with metabolism.

SummaryNon-alcoholic fatty liver disease (NAFLD) is the most prevalent liver disease worldwide, and a major cause of liver cirrhosis and hepatocellular carcinoma. NAFLD is intimately linked with other metabolic disorders characterized by insulin resistance. Metabolic diseases are driven by chronic inflammatory processes, in which macrophages perform essential roles. The polarization status of macrophages is itself influenced by metabolic stimuli such as fatty acids, which in turn affect the progression of metabolic dysfunction at multiple disease stages and in various tissues. For instance, adipose tissue macrophages respond to obesity, adipocyte stress and dietary factors by a specific metabolic and inflammatory programme that stimulates disease progression locally and in the liver. Kupffer cells and monocyte-derived macrophages represent ontologically distinct hepatic macrophage populations that perform a range of metabolic functions. These macrophages integrate signals from the gut-liver axis (related to dysbiosis, reduced intestinal barrier integrity, endotoxemia), from overnutrition, from systemic low-grade inflammation and from the local environment of a steatotic liver. This makes them central players in the progression of NAFLD to steatohepatitis (non-alcoholic steatohepatitis or NASH) and fibrosis. Moreover, the particular involvement of Kupffer cells in lipid metabolism, as well as the inflammatory activation of hepatic macrophages, may pathogenically link NAFLD/NASH and cardiovascular disease. In this review, we highlight the polarization, classification and function of macrophage subsets and their interaction with metabolic cues in the pathophysiology of obesity and NAFLD. Evidence from animal and clinical studies suggests that macrophage targeting may improve the course of NAFLD and related metabolic disorders.

Differential Sensitivity of Kupffer Cells and Hepatic Monocyte-Derived Macrophages to Bacterial Lipopolysaccharide.

The liver contains two distinct populations of macrophages, monocyte-derived macrophages (MDMs), which primarily reside proximal to the Glisson’s capsule and Kupffer cells, which reside within the sinusoids. Kupffer cells infiltrate the liver during embryogenesis and are replenished from local proliferation of mature Kupffer cells. By contrast MDMs arise from hematopoietic stem cells in the bone marrow and are replenishedfrom circulating monocytes. Studies have revealed that these two hepatic macrophage populations possess distinct transcriptomic profiles, suggesting that they may be functionally distinct. In the present study, we tested the hypothesis that MDMs and Kupffer cells are differentially sensitive to bacterial lipopolysaccharide (LPS). MDMs and Kupffer cells were purified to greater than 90% from the livers of mice by using magnetic beads labeled with Cx3cr1 antibody for MDMs and F4/80 antibody for Kupffer cells. Basal levels of tumor necrosis factor-α (TNF-α) mRNA were higher in MDMs when compared to Kupffer cells. After treatment with LPS, mRNA levels of TNF-α, Cxcll, and Cxcl2 were increased to a greater extent in MDMs when compared to Kupffer cells. To confirm these findings, Kupffer cells and MDMs were isolated from mice in which bone marrow transplantation was used to selectively tag cells arising from hematopoietic stem cells in adult mice. Similar to above, treatment of MDMs with LPS increased TNF-α, Cxcll, and Cxcl2 to a greater extent when compared to Kupffer cells. Collectively, these results indicate that MDMs exhibit a greater pro-inflammatory phenotype in the liver when exposed to LPS.

Macrophages in the Aging Liver and Age-Related Liver Disease.

The number of individuals aged 65 or older is projected to increase globally from 524 million in 2010 to nearly 1. 5 billion in 2050. Aged individuals are particularly at risk for developing chronic illness, while being less able to regenerate healthy tissue and tolerate whole organ transplantation procedures. In the liver, these age-related diseases include non-alcoholic fatty liver disease, alcoholic liver disease, hepatitis, fibrosis, and cirrhosis. Hepatic macrophages, a population comprised of both Kupffer cells and infiltrating monocyte derived macrophages, are implicated in several chronic liver diseases and also play important roles in the homeostatic functions of the liver. The effects of aging on hepatic macrophage population dynamics, polarization, and function are not well understood. Studies performed on macrophages derived from other aged sources, such as the bone marrow, peritoneal cavity, lungs, and brain, demonstrate general reductions in autophagy and phagocytosis, dysfunction in cytokine signaling, and altered morphology and distribution, likely mediated by epigenetic changes and mitochondrial defects, that may be applicable to hepatic macrophages. This review highlights recent findings in macrophage developmental biology and function, particularly in the liver, and discusses the role of macrophages in various age-related liver diseases. A better understanding of the biology of aging that influences hepatic macrophages and thus the progression of chronic liver disease will be crucial in order to develop new interventions and treatments for liver disease in aging populations.

Schistosoma mansoni Infection-Induced Transcriptional Changes in Hepatic Macrophage Metabolism Correlate With an Athero-Protective Phenotype.

Hepatic macrophages play an essential role in the granulomatous response to infection with the parasitic helminth Schistosoma mansoni, but the transcriptional changes that underlie this effect are poorly understood. To explore this, we sorted the two previously recognized hepatic macrophage populations (perivascular and Kupffer cells) from naïve and S. mansoni-infected male mice and performed microarray analysis as part of the Immunological Genome Project. The two hepatic macrophage populations exhibited remarkably different genomic profiles. However, this diversity was substantially reduced following infection with S. mansoni, and in fact, both populations demonstrated increases in transcripts of the monocyte lineage, suggesting that both populations may be replenished by monocytes following infection. Pathway analysis showed a profound alteration in global metabolic pathways, including changes to phospholipid and cholesterol metabolism, as well as amino acid biosynthesis and glucagon signaling. These changes suggest a possible mechanism for the previously reported athero-protective effects of S. mansoni infection. Indeed, we find that male ApoE null mice fed a high-fat diet in combination with S. mansoni infection have reduced plaque area and increased glucose tolerance as compared to control mice. Transcript analysis of infected and control high-fat diet fed ApoE−/− mice confirm that ApoC1, Psat1, and Gys1 are all altered by infection, suggesting that altered hepatic macrophage metabolism is associated with S. mansoni- induced protection from hyperlipidemia, atherosclerosis, and glucose intolerance. These results suggest a previously unknown and unreported role of hepatic macrophages in the modulation of whole body lipid and glucose metabolism during infection and provide a template for examining the role of immunomodulation on the long-term metabolism of the host.

The role of hepatic macrophages in liver metastasis

The liver is a major target organ for metastasis of both gastrointestinal and extra-gastrointestinal cancers. Due to its frequently inoperable nature, liver metastasis represents a leading cause of cancer-associated death worldwide. In the past years, the pivotal role of the immune system in this process is being increasingly recognised. In particular, the role of the hepatic macrophages, both recruited monocyte-derived macrophages (Mo-Mfs) and tissue-resident Kupffer cells (KCs), has been shown to be more versatile than initially imagined. However, the lack of tools to easily distinguish between these two macrophage populations has hampered the assignment of particular functionalities to specific hepatic macrophage subsets.In this Review, we highlight the most remarkable findings regarding the origin and functions of hepatic macrophage populations, and we provide a detailed description of their distinct roles in the different phases of the liver metastatic process.

THU-520 - Evolving alterations of hepatic macrophage population in the disease progression of non-alcoholic ateatohepatitis in a mouse model

THU-520 - Evolving alterations of hepatic macrophage population in the disease progression of non-alcoholic ateatohepatitis in a mouse model

Distinct Hepatic Macrophage Populations in Lean and Obese Mice

Obesity is a complex metabolic disorder associated with the development of non-communicable diseases such as cirrhosis, non-alcoholic fatty liver disease, and type 2 diabetes. In humans and rodents, obesity promotes hepatic steatosis and inflammation, which leads to increased production of pro-inflammatory cytokines and acute-phase proteins. Liver macrophages (resident as well as recruited) play a significant role in hepatic inflammation and insulin resistance (IR). Interestingly, depletion of hepatic macrophages protects against the development of high-fat-induced steatosis, inflammation, and IR. Kupffer cells (KCs), liver-resident macrophages, are the first-line defense against invading pathogens, clear toxic or immunogenic molecules, and help to maintain the liver in a tolerogenic immune environment. During high fat diet feeding and steatosis, there is an increased number of recruited hepatic macrophages (RHMs) in the liver and activation of KCs to a more inflammatory or M1 state. In this review, we will focus on the role of liver macrophages (KCs and RHMs) during obesity.

Transient effects of empty liposomes on hepatic macrophage populations in rats.

Liposomes have been used as a vehicle for encapsulating chemicals or toxins in toxicological studies. We investigated the transient effects of empty liposomes on hepatic macrophages by applying a single intravenous injection at a dose of 10 ml/kg body weight in 6-week-old male F344 rats. One day after injection, the numbers of hepatic macrophages reacting to CD163, CD68, Iba-1, MHC class II, Gal-3 and CD204 were significantly increased in liposome-treated rats. CD163+ Kupffer cells and CD68+ macrophages with increased phagocytic activity in hepatic lobules were most sensitive. The histological architecture of the liver was not changed following liposome injection; however, hepatocytes showed increased proliferating activity, demonstrable with proliferation marker immunostaining and by an increase in gene profiles related to the cell cycle. In the liposome-treated rats, interestingly, AST and ALT values were significantly decreased, and MCP-1, IL-1β and TGF-β1 mRNAs were significantly increased. Collectively, the present study found that hepatic macrophages activated by liposomes can influence liver homeostasis. This information would be useful for background studies on liposomes.