Role of Kupffer cells in the pathogenesis of liver disease (original) (raw)
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REVIEW Role of the Kupffer Cell in Mediating Hepatic Toxicity and Carcinogenesis
2007
Kupffer cells are resident macrophages of the liver and play an important role in its normal physiology and homeostasis as well as participating in the acute and chronic responses of the liver to toxic compounds. Activation of Kupffer cells directly or indirectly by toxic agents results in the release of an array of inflammatory mediators, growth factors, and reactive oxygen
Distinct development and functions of resident and recruited liver Kupffer cells/macrophages
Journal of Leukocyte Biology, 2013
Although mouse liver F4/80 ϩ Kupffer cells consist of cytokine-producing CD11b ϩ cells and phagocytic CD68 ϩ cells, an undefined CD11b Ϫ CD68 Ϫ subset (30%) also exists. We herein demonstrate a more fundamental classification by adding CD32 (Fc␥RII), which covers most liver F4/80 ϩ cells and the distinct functions of them. Among the F4/80 ϩ cells, 50%, 40%, and 30% of cells were CD32 ϩ , CD68 ϩ , and CD11b ϩ , respectively, and one-half of the CD68 ϩ cells coexpressed CD32. CD68 ϩ and CD32 ϩ cells, but not CD11b ϩ cells, expressed a phagocytosis-related CRIg. Gy (6) irradiation depleted liver CD11b ϩ cells and those in the spleen, bone marrow, and peripheral blood but not liver CD32/ CD68 ϩ cells. Transfer of bone marrow cells into the irradiated mice reconstituted liver CD11b ϩ cells. Conversely, clodronate pretreatment depleted only liver CD32/CD68 ϩ cells but not liver CD11b ϩ cells and peripheral blood or spleen CD11b ϩ monocytes/macrophages. Moreover, the CD32 ϩ cells might be precursors of CD68 ϩ cells, as a large proportion of CD32 ϩ cells expressed the c-kit (CD117), and CD34 and CD32 ϩ cells acquired CD68 immediately after bacteria administration. CD32/CD68 ϩ cells, but not CD11b ϩ cells, expressed resident macrophage-specific MerTK and CD64 (Fc␥RI). Challenge with Staphylococcus aureus or liver metastatic EL-4 tumor cells indicated that the CD68 ϩ subset is engaged in systemic bactericidal activity, whereas the CD11b ϩ subset is pivotal for liver antitumor immunity. Human liver CD14 ϩ Kupffer cells could also be classified into three similar subsets. These results suggest that liver CD68 ϩ Kupffer cells and CD11b ϩ Kupffer cells/macrophages are developmentally and functionally distinct subsets.
Laboratory …, 2010
Hepatocellular apoptosis, hepatic inflammation, and fibrosis are prominent features in chronic liver diseases. However, the linkage among these processes remains mechanistically unclear. In this study, we examined the apoptosis and activation of Kupffer cells (KCs) as well as their pathophysiological involvement in liver fibrosis process. Hepatic fibrosis was induced in rats by dimethylnitrosamine (DMN) or carbon tetrachloride (CCl4) treatment. KCs were isolated from normal rats and incubated with lipopolysaccharide (LPS) or from fibrotic rats. The KCs were stained immunohistochemically with anti-CD68 antibody, a biomarker for KC. The level of expression of CD68 was analyzed by western blot and real-time PCR methods. The apoptosis and pathophysiological involvement of KCs in the formation of liver fibrosis were studied using confocal microscopy. The mRNA and protein expression of CD68 were significantly increased in DMNand CCL4-treated rats. Confocal microscopy analysis showed that CD68-positive KCs, but not a-smooth muscle actin (SMA)-positive cells, underwent apoptosis in the liver of DMN-and CCL4-treated rats. It was also revealed that the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling and CD68-double-positive apoptotic KCs located in the portal or fibrotic septa area were situated next to hepatic stellate cells (HSCs). Tumor necrosis factor-a (TNF-a) and KC co-localized in the liver in the neighbor of HSCs. The double a-SMAand collagen type I-positive cells predominantly existed in fibrotic septa, and those cells were co-localized clearly with CD68-positive cells. Interestingly, some CD68 and Col (1) double positive, but completely negative for a-SMA, were found in the portal areas and hepatic sinusoids; this phenomenon was also validated in primary isolated KCs after 6 h LPS exposure or fibrotic rats in vitro. These results show that KCs are associated with hepatocellular apoptosis, inflammation, and fibrosis process in a liver fibrosis models.
Kupffer cells (KCs) are widely considered important contributors to liver injury during viral hepatitis due to their proinflammatory activity. Herein we utilized hepatitis B virus (HBV)-replication competent transgenic mice and wild-type mice infected with a hepatotropic adenovirus to demonstrate that KCs do not directly induce hepatocellular injury nor do they affect the pathogenic potential of virus-specific CD8 T cells. Instead, KCs limit the severity of liver immunopathology. Mechanistically, our results are most compatible with the hypothesis that KCs contain liver immunopathology by removing apoptotic hepatocytes in a manner largely dependent on scavenger receptors. Apoptotic hepatocytes not readily removed by KCs become secondarily necrotic and release high-mobility group box 1 (HMGB-1) protein, promoting organ infiltration by inflammatory cells, particularly neutrophils. Overall, these results indicate that KCs resolve rather than worsen liver immunopathology.
Kupffer Cells Hasten Resolution of Liver Immunopathology in Mouse Models of Viral Hepatitis
PLoS Pathogens, 2011
Kupffer cells (KCs) are widely considered important contributors to liver injury during viral hepatitis due to their proinflammatory activity. Herein we utilized hepatitis B virus (HBV)-replication competent transgenic mice and wild-type mice infected with a hepatotropic adenovirus to demonstrate that KCs do not directly induce hepatocellular injury nor do they affect the pathogenic potential of virus-specific CD8 T cells. Instead, KCs limit the severity of liver immunopathology. Mechanistically, our results are most compatible with the hypothesis that KCs contain liver immunopathology by removing apoptotic hepatocytes in a manner largely dependent on scavenger receptors. Apoptotic hepatocytes not readily removed by KCs become secondarily necrotic and release high-mobility group box 1 (HMGB-1) protein, promoting organ infiltration by inflammatory cells, particularly neutrophils. Overall, these results indicate that KCs resolve rather than worsen liver immunopathology.
The role of Kupffer cells in hepatitis B and hepatitis C virus infections
Journal of Hepatology, 2014
Globally, over 500 million people are chronically infected with the hepatitis B virus (HBV) or hepatitis C virus (HCV). These chronic infections cause liver inflammation, and may result in fibrosis/cirrhosis or hepatocellular carcinoma. Albeit that HBV and HCV differ in various aspects, clearance, persistence, and immunopathology of either infection depends on the interplay between the innate and adaptive responses in the liver. Kupffer cells, the liver-resident macrophages, are abundantly present in the sinusoids of the liver. These cells have been shown to be crucial players to maintain homeostasis, but also contribute to pathology. However, it is important to note that especially during pathology, Kupffer cells are difficult to distinguish from infiltrating monocytes/macrophages and other myeloid cells. In this review we discuss our current understanding of Kupffer cells, and assess their role in the regulation of anti-viral immunity and disease pathogenesis during HBV and HCV infection.
Cytokinetic Analysis of the Expanding Kupffer-Cell Population Inrat Liver
Cell Proliferation, 1986
Zymosan stimulation in rats provides a useful model for studying the expansion of the Kupffer-cell population in liver, which represents the major population of tissue macrophages. This study, using tritiated-thymidine-labelling experiments, demonstrates that during population expansion at least 90% of the resident macrophages (Kupffer cells) develop proliferative activity. The mean duration of the cell cycle is estimated to be 52 hr, with an S phase of 7 hr. We have calculated that about 75% of population expansion results from local Kupffer-cell replication, whereas the remaining growth results from extrahepatic recruitment of macrophage precursors. These findings conflict with a concept of the mononuclear phagocyte system, which states that resident macrophages are (monocyte-derived) non-dividing end-cells. Macrophage populations in several organs are known to increase in size after stimulation by a variety of inflammatory agents (