Although iron is a vital component in the body, excessive iron leads to iron toxicity, which affects vital organs. In particular, the liver is considerably affected by iron toxicity because it stores the highest amount of iron in the body. Nonetheless, the relationship between iron overload and aging in the liver has not yet been clearly identified. This study aimed to observe the effects of aging on iron overload in the liver. Female C57BL/6J mice were randomly divided into vehicle control and iron overload groups (n = 7-22 per group). The iron overload group was injected with iron-dextran (Fe-dextran, ferric hydroxide dextran complex) (0.5 g/kg) for 4 weeks. After the experimental period, liver and blood samples were obtained from 2-, 15-, and 22-month-old mice. Liver weight, iron deposition, structural changes, cell death, extracellular matrix deposition, and fenestration of sinusoidal vessels were analyzed and compared between the groups. Additionally, biochemical analyses (aspartate aminotransferase, alanine aminotransferase, and serum total iron levels) were performed. The iron overload group exhibited significant differences compared with the control group with age. In the elderly iron overload model, iron deposition, inflammatory cell infiltration, and cell death were significantly increased (p < 0.0001). Moreover, deposition of the extracellular matrix and defenestration of sinusoidal fenestrae were observed among 22-month-old mice in the iron overload group. These results suggest that aging is a risk factor for iron-induced liver injury. Therefore, caution should be exercised when performing iron-related treatments in the elderly.

Metabolic dysfunction-associated steatohepatitis (MASH) is characterized by injury to steatotic hepatocytes that triggers the release of endogenous danger-associated molecular patterns. Recent work demonstrated that exposed lipid droplets (LDs) serve as a pathogenic signal that promotes monocyte infiltration and its maturation into triggering receptor expressed in myeloid cells 2 (TREM2+) macrophages in MASH liver. Here we explore the role of LD exposure in modulating inflammatory signaling in macrophages. We found that LD efferocytosis triggers a global transcriptional response and dampens pro-inflammatory signaling in macrophages. LD treatment attenuated NLRP3 inflammasome activation via mechanisms independent of lysosomal LD hydrolysis. While TREM2 was dispensable for LD efferocytosis by macrophages, it was required for the attenuation of proinflammatory signaling upon LD exposure. Additionally, MS4A7 downregulation contributes to LD efferocytosis-mediated dampening of inflammatory response. These results underscore the dual role of LD exposure in MASH liver by promoting monocyte infiltration and TREM2+ macrophage induction, while restraining proinflammatory response in macrophages.

Macrophages play crucial roles in immune response and tissue homeostasis, with their functions becoming increasingly complex in obesity-mediated metabolic disorders. This review explores the extensive range of macrophage activities within adipose and liver tissues, emphasizing their contribution to the pathogenesis and progression of obesity and its related metabolic dysfunction-associated steatotic liver disease (MASLD). In the context of obesity, macrophages respond adaptively to lipid overloads and inflammatory cues in adipose tissue, profoundly influencing insulin resistance and metabolic homeostasis. Concurrently, their role in the liver extends to moderating inflammation and orchestrating fibrotic responses, integral to the development of MASLD. Highlighting the spectrum of macrophage phenotypes across these metabolic landscapes, we summarize their diverse roles in linking inflammatory processes with metabolic functions. This review advocates for a deeper understanding of macrophage subsets in metabolic tissues, proposing targeted research to harness their therapeutic potential in mitigating MASLD and other metabolic disorders.

Introduction: Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) stems from disrupted lipid metabolism in the liver, often linked to obesity, type 2 diabetes, and dyslipidemia. In Mexico, where obesity affects 36.9% of adults, MASLD prevalence has risen, especially with metabolic syndrome affecting 56.31% by 2018. MASLD can progress to Metabolic Dysfunction-Associated Steatohepatitis (MASH), affecting 5.27% globally, leading to severe complications like cirrhosis and hepatocellular carcinoma. Background: Visceral fat distribution varies by gender, impacting MASLD development due to hormonal influences. Insulin resistance plays a central role in MASLD pathogenesis, exacerbated by high-fat diets and specific fatty acids, leading to hepatic steatosis. Lipotoxicity from saturated fatty acids further damages hepatocytes, triggering inflammation and fibrosis progression in MASH. Diagnosing MASLD traditionally involves invasive liver biopsy, but non-invasive methods like ultrasound and transient elastography are preferred due to their safety and availability. These methods detect liver steatosis and fibrosis with reasonable accuracy, offering alternatives to biopsy despite varying sensitivity and specificity. Conclusions: MASLD as a metabolic disorder underscores its impact on public health, necessitating improved awareness and early management strategies to mitigate its progression to severe liver diseases.

Chronic liver diseases, primarily metabolic dysfunction-associated steatotic liver disease (MASLD), harmful use of alcohol, or viral hepatitis, may result in liver fibrosis, cirrhosis, and cancer. Hepatic fibrogenesis is a complex process with interactions between different resident and non-resident heterogeneous liver cell populations, ultimately leading to deposition of extracellular matrix and organ failure. Shifts in cell phenotypes and functions involve pronounced transcriptional and protein synthesis changes that require metabolic adaptations in cellular substrate metabolism, including glucose and lipid metabolism, resembling changes associated with the Warburg effect in cancer cells. Cell activation and metabolic changes are regulated by metabolic stress responses, including the unfolded protein response, endoplasmic reticulum stress, autophagy, ferroptosis, and nuclear receptor signaling. These metabolic adaptations are crucial for inflammatory and fibrogenic activation of macrophages, lymphoid cells, and hepatic stellate cells. Modulation of these pathways, therefore, offers opportunities for novel therapeutic approaches to halt or even reverse liver fibrosis progression.

Macrophages, as important immune cells of the organism, are involved in maintaining intrahepatic microenvironmental homeostasis and can undergo rapid phenotypic changes in the injured or recovering liver. In recent years, the crucial role of macrophage-programmed cell death in the development and regression of liver diseases has become a research hotspot. Moreover, macrophage-targeted therapeutic strategies are emerging in both preclinical and clinical studies. Given the macrophages' vital role in complex organismal environments, there is tremendous academic interest in developing novel therapeutic strategies that target these cells. This review provides an overview of the characteristics and interactions between macrophage polarization, programmed cell death, related biomarkers, and macrophage-targeted therapies. It aims to deepen the understanding of macrophage immunomodulation and molecular mechanisms and to provide a basis for the treatment of macrophage-associated liver diseases.

Cell types with different morphology, and function collaborate to maintain organ function. As such, analyzing proteomic differences and connections between different types of cells forms the foundation for establishing functional connectomes and developing in vitro organoid simulation experiments. However, the efficiency of cell type isolation from organs is limited by time, equipment, and cost. Here, hierarchical dendritic photonic crystal beads (HDPCBs) featuring high-density functional groups via the self-assembly of dendritic mesoporous structure SiO2 nanoparticles (DM-SiO2) and grafting dendrimers onto the surface of dendritic mesoporous photonic crystal beads (DMPCBs) is developed. This platform integrates multitype cell separation with in situ protein cleavage processes. Efficient simultaneous isolation of Kupffer cells and Liver Sinusoidal Endothelial cells (LSECs) from liver, with high specificity and convenient operation in a short separation time are demonstrated. The results reveal 2832 and 3442 unique proteins identified in Kupffer cells and LSECs using only 50 HDPCBs, respectively. 764 and 629 over-expressed proteins associated with the function of Kupffer cells and LSECs are found, respectively. The work offers a new method for efficiently isolating multiple cell types from tissues and downstream proteomic analysis, ultimately facilitating the identification of primary cell compositions and functions.

Non-alcoholic steatohepatitis (NASH), now known as metabolic dysfunction-associated steatohepatitis (MASH), involves oxidative stress caused by the overproduction of reactive oxygen species (ROS). Small-molecule antioxidants have not been approved for antioxidant chemotherapy because of severe adverse effects that collapse redox homeostasis, even in healthy tissues. To overcome these disadvantages, we have been developing poly(ethylene glycol)-block-poly(cysteine) (PEG-block-PCys)-based self-assembling polymer nanoparticles (NanoCyses), releasing Cys after in vivo degradation by endogenous enzymes, to obtain antioxidant effects without adverse effects. However, a comprehensive investigation of the effects of polymer design on therapeutic outcomes has not yet been conducted to develop our NanoCys system for antioxidant chemotherapy. In this study, we synthesized different poly(L-cysteine) (PCys) chains whose sulfanyl groups were protected by tert-butyl thiol (StBu) and butyryl (Bu) groups to change the reactivity of the side chains, affording NanoCys(SS) and NanoCys(Bu), respectively. To elucidate the importance of the polymer design, these NanoCyses were orally administered to MASH model mice as a model of oxidative stress-related diseases. Consequently, the acyl-protective NanoCys(Bu) significantly suppressed hepatic lipid accumulation and oxidative stress compared to NanoCys(SS). Furthermore, we substantiated that shorter PCys were much better than longer PCys for therapeutic outcomes and the effects related to the liberation properties of Cys from these nanoparticles. Owing to its antioxidant functions, NanoCyses also significantly attenuated hepatic inflammation and fibrosis in the MASH mouse model.

Accumulation of lipotoxic lipids, such as free cholesterol, induces hepatocyte death and subsequent inflammation and fibrosis in the pathogenesis of nonalcoholic steatohepatitis (NASH). However, the underlying mechanisms remain unclear. We have previously reported that hepatocyte death locally induces phenotypic changes in the macrophages surrounding the corpse and remnant lipids, thereby promoting liver fibrosis in a murine model of NASH. Here, we demonstrated that lysosomal cholesterol overload triggers lysosomal dysfunction and profibrotic activation of macrophages during the development of NASH. β-cyclodextrin polyrotaxane (βCD-PRX), a unique supramolecule, is designed to elicit free cholesterol from lysosomes. Treatment with βCD-PRX ameliorated cholesterol accumulation and profibrotic activation of macrophages surrounding dead hepatocytes with cholesterol crystals, thereby suppressing liver fibrosis in a NASH model, without affecting the hepatic cholesterol levels. In vitro experiments revealed that cholesterol-induced lysosomal stress triggered profibrotic activation in macrophages predisposed to the steatotic microenvironment. This study provides evidence that dysregulated cholesterol metabolism in macrophages would be a novel mechanism of NASH.

Alcohol-associated liver disease (ALD) is a common chronic liver disease with increasing incidence worldwide. Alcoholic liver steatosis/steatohepatitis can progress to liver fibrosis/cirrhosis, which can cause predisposition to hepatocellular carcinoma. ALD diagnosis and management are confounded by several challenges. Iron loading is a feature of ALD which can exacerbate alcohol-induced liver injury and promote ALD pathologic progression. Knowledge of the mechanisms that mediate liver iron loading can help identify cellular/molecular targets and thereby aid in designing adjunct diagnostic, prognostic, and therapeutic approaches for ALD. Herein, the cellular mechanisms underlying alcohol-induced liver iron loading are reviewed and how excess iron in patients with ALD can promote liver fibrosis and aggravate disease pathology is discussed. Alcohol-induced increase in hepatic transferrin receptor-1 expression and up-regulation of high iron protein in Kupffer cells (proposed) facilitate iron deposition and retention in the liver. Iron is loaded in both parenchymal and nonparenchymal liver cells. Iron-loaded liver can promote ferroptosis and thereby contribute to ALD pathology. Iron and alcohol can independently elevate oxidative stress. Therefore, a combination of excess iron and alcohol amplifies oxidative stress and accelerates liver injury. Excess iron-stimulated hepatocytes directly or indirectly (through Kupffer cell activation) activate the hepatic stellate cells via secretion of proinflammatory and profibrotic factors. Persistently activated hepatic stellate cells promote liver fibrosis, and thereby facilitate ALD progression.

The burden of chronic liver disease is rising substantially worldwide. Fibrosis, characterized by excessive deposition of extracellular matrix proteins, is the common pathway leading to cirrhosis, and limited treatment options are available. There is increasing evidence suggesting the role of cellular stress responses contributing to fibrogenesis. This Review provides an overview of studies that analyse the role of cellular stress in different cell types involved in fibrogenesis, including hepatocytes, hepatic stellate cells, liver sinusoidal endothelial cells and macrophages.

Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are emerging as the leading causes of liver disease worldwide. These conditions can lead to cirrhosis, liver cancer, liver failure, and other related ailments. At present, liver transplantation remains the sole treatment option for end-stage NASH, leading to a rapidly growing socioeconomic burden. Kupffer cells (KCs) are a dominant population of macrophages that reside in the liver, playing a crucial role in innate immunity. Their primary function includes phagocytosing exogenous substances, presenting antigens, and triggering immune responses. Moreover, they interact with other liver cells during the pathogenesis of NAFLD, and this crosstalk may either delay or exacerbate disease progression. Stimulation by endogenous signals triggers the activation of KCs, resulting in the expression of various inflammatory factors and chemokines, such as NLRP3, TNF-α, IL-1B, and IL-6, and contributing to the inflammatory cascade. In the past 5 years, significant advances have been made in understanding the biological properties and immune functions of KCs in NAFLD, including their interactions with tissue molecules, underlying molecular mechanisms, signaling pathways, and relevant therapeutic interventions. Having a comprehensive understanding of these mechanisms and characteristics can have enormous potential in guiding future strategies for the prevention and treatment of NAFLD.

Macrophages undergo plasma membrane fusion and cell multinucleation to form multinucleated giant cells (MGCs) such as osteoclasts in bone, Langhans giant cells (LGCs) as part of granulomas or foreign-body giant cells (FBGCs) in reaction to exogenous material. How multinucleation per se contributes to functional specialization of mature mononuclear macrophages remains poorly understood in humans. Here, we integrate comparative transcriptomics with functional assays in purified mature mononuclear and multinucleated human osteoclasts, LGCs and FBGCs. Strikingly, in all three types of MGCs, multinucleation causes a pronounced downregulation of macrophage identity. We show enhanced lysosome-mediated intracellular iron homeostasis promoting MGC formation. The transition from mononuclear to multinuclear state is accompanied by cell specialization specific to each polykaryon. Enhanced phagocytic and mitochondrial function associate with FBGCs and osteoclasts, respectively. Moreover, human LGCs preferentially express B7-H3 (CD276) and can form granuloma-like clusters in vitro, suggesting that their multinucleation potentiates T cell activation. These findings demonstrate how cell-cell fusion and multinucleation reset human macrophage identity as part of an advanced maturation step that confers MGC-specific functionality.

Complications of the liver are amongst the world's worst diseases. Liver fibrosis is the first stage of liver problems, while cirrhosis is the last stage, which can lead to death. The creation of effective anti-fibrotic drug delivery methods appears critical due to the liver's metabolic capacity for drugs and the presence of insurmountable physiological impediments in the way of targeting. Recent breakthroughs in anti-fibrotic agents have substantially assisted in fibrosis; nevertheless, the working mechanism of anti-fibrotic medications is not fully understood, and there is a need to design delivery systems that are well-understood and can aid in cirrhosis. Nanotechnology-based delivery systems are regarded to be effective but they have not been adequately researched for liver delivery. As a result, the capability of nanoparticles in hepatic delivery was explored. Another approach is targeted drug delivery, which can considerably improve efficacy if delivery systems are designed to target hepatic stellate cells (HSCs). We have addressed numerous delivery strategies that target HSCs, which can eventually aid in fibrosis. Recently genetics have proved to be useful, and methods for delivering genetic material to the target place have also been investigated where different techniques are depicted. To summarize, this review paper sheds light on the most recent breakthroughs in drug and gene-based nano and targeted delivery systems that have lately shown useful for the treatment of liver fibrosis and cirrhosis.

The molecular pathogenesis of nonalcoholic steatohepatitis (NASH) includes a complex interaction of metabolic stress and inflammatory stimuli. Considering the therapeutic goals of NASH, it is important to determine whether the treatment can prevent the progression from NASH to hepatocellular carcinoma. Taxifolin, also known as dihydroquercetin, is a natural bioactive flavonoid with antioxidant and anti-inflammatory properties commonly found in various foods and health supplement products. In this study, we demonstrated that Taxifolin treatment markedly prevented the development of hepatic steatosis, chronic inflammation, and liver fibrosis in a murine model of NASH. Its mechanisms include a direct action on hepatocytes to inhibit lipid accumulation. Taxifolin also increased brown adipose tissue activity and suppressed body weight gain through at least two distinct pathways: direct action on brown adipocytes and indirect action via fibroblast growth factor 21 production in the liver. Notably, the Taxifolin treatment after NASH development could effectively prevent the development of liver tumors. Collectively, this study provides evidence that Taxifolin shows pleiotropic effects for the treatment of the NASH continuum. Our data also provide insight into the novel mechanisms of action of Taxifolin, which has been widely used as a health supplement with high safety.

Hyaluronan receptor LYVE-1 is expressed by liver sinusoidal endothelial cells (LSEC), lymphatic endothelial cells and specialized macrophages. Besides binding to hyaluronan, LYVE-1 can mediate adhesion of leukocytes and cancer cells to endothelial cells. Here, we assessed the impact of LYVE-1 on physiological liver functions and metastasis.

Mice with deficiency of Lyve-1 (Lyve-1-KO) were analyzed using histology, immunofluorescence, microarray analysis, plasma proteomics and flow cytometry. Liver metastasis was studied by intrasplenic/intravenous injection of melanoma (B16F10 luc2, WT31) or colorectal carcinoma (MC38).

Hepatic architecture, liver size, endothelial differentiation and angiocrine functions were unaltered in Lyve-1-KO. Hyaluronan plasma levels were significantly increased in Lyve-1-KO. Besides, plasma proteomics revealed increased carbonic anhydrase-2 and decreased FXIIIA. Furthermore, gene expression analysis of LSEC indicated regulation of immunological pathways. Therefore, liver metastasis of highly and weakly immunogenic tumors, i.e. melanoma and colorectal carcinoma (CRC), was analyzed. Hepatic metastasis of B16F10 luc2 and WT31 melanoma cells, but not MC38 CRC cells, was significantly reduced in Lyve-1-KO mice. In vivo retention assays with B16F10 luc2 cells were unaltered between Lyve-1-KO and control mice. However, in tumor-free Lyve-1-KO livers numbers of hepatic CD4⁺, CD8⁺ and regulatory T cells were increased. In addition, iron deposition was found in F4/80⁺ liver macrophages known to exert pro-inflammatory effects.

Lyve-1 deficiency controlled hepatic metastasis in a tumor cell-specific manner leading to reduced growth of hepatic metastases of melanoma, but not CRC. Anti-tumorigenic effects are likely due to enhancement of the premetastatic hepatic immune microenvironment influencing early liver metastasis formation.

Non-alcoholic fatty liver disease (NAFLD) has become the most common cause of chronic liver disease worldwide, and is closely associated with the increased risk of the prevalence of obesity and diabetes. NAFLD begins with the presence of >5% excessive lipid accumulation in the liver, and potentially develops into non-alcoholic steatohepatitis, fibrosis, cirrhosis and hepatocellular carcinoma. Therefore, insight into the pathogenesis of NAFLD is of key importance to its effective treatment. Iron is an essential element in the life of all mammalian organisms. However, the free iron deposition is positively associated with histological severity in NAFLD patients due to the production of reactive oxygen species via the Fenton reaction. Recently, several iron metabolism-targeted therapies, such as phlebotomy, iron chelators, nanotherapeutics. and ferroptosis, have shown their potential as a therapeutic option in the treatment of NAFLD and as a clinical strategy to intervene in the progression of NAFLD. Herein, we review the recent overall evidence on iron metabolism and provide the mechanism of hepatic iron overload-induced liver pathologies and the recent advances in iron metabolism-targeted therapeutics in the treatment of NAFLD.

Resident macrophages play a unique role in the maintenance of tissue function. As phagocytes, they are an essential first line defenders against pathogens and much of the initial characterization of these cells was focused on their interaction with viral and bacterial pathogens. However, these cells are increasingly recognized as contributing to more than just host defense. Through cytokine production, receptor engagement and gap junction communication resident macrophages tune tissue inflammatory tone, influence adaptive immune cell phenotype and regulate tissue structure and function. This review highlights resident macrophages in the liver and lung as they hold unique roles in the maintenance of the interface between the circulatory system and the external environment. As such, we detail the developmental origin of these cells, their contribution to host defense and the array of tools these cells use to regulate tissue homeostasis.

Kupffer cells (KCs), the largest tissue-resident macrophage population in the body, play a central role in maintaining a delicate balance between immune tolerance and immunity in the liver. However, the underlying molecular mechanism remains elusive. In this study, we show that KCs express high levels of miR-146a, which is under control of the PU.1 transcription factor. miR-146a deficiency promoted KCs differentiation toward a proinflammatory phenotype; conversely, miR-146a overexpression suppressed this phenotypic differentiation. We found that hepatitis B virus (HBV) persistence or HBV surface Ag treatment significantly upregulated miR-146a expression and thereby impaired polarization of KCs toward a proinflammatory phenotype. Furthermore, in an HBV carrier mouse model, KCs depletion by clodronate liposomes dramatically promoted HBV clearance and enhanced an HBV-specific hepatic CD8⁺ T cell and CD4⁺ T cell response. Consistent with this finding, miR-146a knockout mice cleared HBV faster and elicited a stronger adaptive antiviral immunity than wild-type mice. In vivo IL-12 blockade promoted HBV persistence and tempered the HBV-specific CTL response in the liver of miR-146a knockout mice. Taken together, our results identified miR-146a as a critical intrinsic regulator of an immunosuppressive phenotype in KCs under inflammatory stimuli, which may be beneficial in maintenance of liver homeostasis under physiological condition. Meanwhile, during HBV infection, miR-146a contributed to viral persistence by inhibiting KCs proinflammatory polarization, highlighting its potential as a therapeutic target in HBV infection.

Nonalcoholic fatty liver disease (NAFLD), a spectrum of metabolic liver disease associated with obesity, ranges from relatively benign hepatic steatosis to nonalcoholic steatohepatitis (NASH). The latter is characterized by persistent liver injury, inflammation, and liver fibrosis, which collectively increase the risk for end-stage liver diseases such as cirrhosis and hepatocellular carcinoma. Recent work has shed new light on the pathophysiology of NAFLD/NASH, particularly the role of genetic, epigenetic, and dietary factors and metabolic dysfunctions in other tissues in driving excess hepatic fat accumulation and liver injury. In parallel, single-cell RNA sequencing studies have revealed unprecedented details of the molecular nature of liver cell heterogeneity, intrahepatic cross talk, and disease-associated reprogramming of the liver immune and stromal vascular microenvironment. This review covers the recent advances in these areas, the emerging concepts of NASH pathogenesis, and potential new therapeutic opportunities. Expected final online publication date for the Annual Review of Nutrition, Volume 42 is August 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Hepatic fibrosis is a common pathological process involving persistent liver injury with various etiologies and subsequent inflammatory responses that occur in chronic liver diseases. If left untreated, liver fibrosis can progress to liver cirrhosis, hepatocellular carcinoma and eventually, liver failure. Unfortunately, to date, there is no effective treatment for liver fibrosis, with the exception of liver transplantation. Although the pathophysiology of liver fibrosis is multifactorial and includes the activation of hepatic stellate cells, which are known to drive liver fibrogenesis, hepatic macrophages have emerged as central players in the development of liver fibrosis and regression. Hepatic macrophages, which consist of resident macrophages (Kupffer cells) and monocyte-derived macrophages, have been shown to play an intricate role in the initiation of inflammatory responses to liver injury, progression of fibrosis, and promotion of fibrosis resolution. These features have made hepatic macrophages uniquely attractive therapeutic targets in the fight against hepatic fibrosis. In this review, we synthesised the literature to highlight the functions and regulation of heterogeneity in hepatic macrophages. Furthermore, using the existing findings, we attempt to offer insights into the molecular mechanisms underlying the phenotypic switch from fibrogenic macrophages to restorative macrophages, the regulation of heterogeneity, and modes of action for hepatic macrophages. A better understanding of these mechanisms may guide the development of novel anti-fibrotic therapies (eg macrophage subset-targeted treatments) to combat liver fibrosis in the future.

The liver is an essential immunological organ due to its gatekeeper position to bypassing antigens from the intestinal blood flow and microbial products from the intestinal commensals. The tissue-resident liver macrophages, termed Kupffer cells, represent key phagocytes that closely interact with local parenchymal, interstitial and other immunological cells in the liver to maintain homeostasis and tolerance against harmless antigens. Upon liver injury, the pool of hepatic macrophages expands dramatically by infiltrating bone marrow-/monocyte-derived macrophages. The interplay of the injured microenvironment and altered macrophage pool skews the subsequent course of liver injuries. It may range from complete recovery to chronic inflammation, fibrosis, cirrhosis and eventually hepatocellular cancer. This review summarizes current knowledge on the classification and role of hepatic macrophages in the healthy and injured liver.