Similar Datasets
Project description:Metabolic-associated fatty liver disease (MAFLD) represents a spectrum of disease states ranging from simple steatosis to non-alcoholic steatohepatitis (NASH). Hepatic macrophages, specifically Kupffer cells (KCs), are suggested to play important roles in the pathogenesis of MAFLD through their activation, although the exact roles played by these cells remain unclear. Here, we demonstrated that KCs were reduced in MAFLD being replaced by macrophages originating from the bone marrow. Recruited macrophages existed in two subsets with distinct activation states, either closely resembling homeostatic KCs or lipid-associated macrophages (LAMs) from obese adipose tissue. Hepatic LAMs expressed Osteopontin, a biomarker for patients with NASH, linked with the development of fibrosis. Fitting with this, LAMs were found in regions of the liver with reduced numbers of KCs, characterized by increased Desmin expression. Together, our data highlight considerable heterogeneity within the macrophage pool and suggest a need for more specific macrophage targeting strategies in MAFLD.
| S-EPMC7501731 | biostudies-literature
Project description:CITE-seq analysis on total CD45+ cells isolated from the livers of mice fed a standard diet (SD) or western diet (WD; fat, cholesterol and sugar) for 12, 24 and 36 weeks. We also performed single cell RNA sequencing analysis of the CD45- cells isolated from the livers of the mice fed the SD or WD for 24 and 36 weeks.
2020-08-18 | GSE156052 | GEO
Project description:CITE-seq analysis on total CD45+ cells isolated from the livers of mice fed a standard diet (SD) or western diet (WD; fat, cholesterol and sugar) for 12, 24 and 36 weeks. We also performed single cell RNA sequencing analysis of the CD45- cells isolated from the livers of the mice fed the SD or WD for 24 and 36 weeks.
2020-08-18 | GSE156057 | GEO
Project description:Osteopontin expression identifies a subset of recruited macrophages distinct from Kupffer cells in the fatty liver.
| PRJNA656551 | ENA
Project description:Osteopontin expression identifies a subset of recruited macrophages distinct from Kupffer cells in the fatty liver. [Bulk RNA Seq]
| PRJNA656542 | ENA
Project description:Osteopontin expression identifies a subset of recruited macrophages distinct from Kupffer cells in the fatty liver. [Single cell RNA Seq]
| PRJNA656554 | ENA
Project description:UnlabelledDue to a scarcity of immunocompetent animal models for viral hepatitis, little is known about the early innate immune responses in the liver. In various hepatotoxic models, both pro- and anti-inflammatory activities of recruited monocytes have been described. In this study, we compared the effect of liver inflammation induced by the Toll-like receptor 4 ligand lipopolysaccharide (LPS) with that of a persistent virus, lymphocytic choriomeningitis virus (LCMV) clone 13, on early innate intrahepatic immune responses in mice. LCMV infection induces a remarkable influx of inflammatory monocytes in the liver within 24 h, accompanied by increased transcript levels of several proinflammatory cytokines and chemokines in whole liver. Importantly, while a single LPS injection results in similar recruitment of inflammatory monocytes to the liver, the functional properties of the infiltrating cells are dramatically different in response to LPS versus LCMV infection. In fact, intrahepatic inflammatory monocytes are skewed toward a secretory phenotype with impaired phagocytosis in LCMV-induced liver inflammation but exhibit increased endocytic capacity after LPS challenge. In contrast, F4/80(high)-Kupffer cells retain their steady-state endocytic functions upon LCMV infection. Strikingly, the gene expression levels of inflammatory monocytes dramatically change upon LCMV exposure and resemble those of Kupffer cells. Since inflammatory monocytes outnumber Kupffer cells 24 h after LCMV infection, it is highly likely that inflammatory monocytes contribute to the intrahepatic inflammatory response during the early phase of infection. Our findings are instrumental in understanding the early immunological events during virus-induced liver disease and point toward inflammatory monocytes as potential target cells for future treatment options in viral hepatitis.ImportanceInsights into how the immune system deals with hepatitis B virus (HBV) and HCV are scarce due to the lack of adequate animal model systems. This knowledge is, however, crucial to developing new antiviral strategies aimed at eradicating these chronic infections. We model virus-host interactions during the initial phase of liver inflammation 24 h after inoculating mice with LCMV. We show that infected Kupffer cells are rapidly outnumbered by infiltrating inflammatory monocytes, which secrete proinflammatory cytokines but are less phagocytic. Nevertheless, these recruited inflammatory monocytes start to resemble Kupffer cells on a transcript level. The specificity of these cellular changes for virus-induced liver inflammation is corroborated by demonstrating opposite functions of monocytes after LPS challenge. Overall, this demonstrates the enormous functional and genetic plasticity of infiltrating monocytes and identifies them as an important target cell for future treatment regimens.
| S-EPMC4403491 | biostudies-literature
Project description:TNF and Fas/FasL are vital components, not only in hepatocyte injury, but are also required for hepatocyte regeneration. Liver F4/80+Kupffer cells are classified into two subsets; resident radio-resistant CD68+cells with phagocytic and bactericidal activity, and recruited radio-sensitive CD11b+cells with cytokine-producing capacity. The aim of this study was to investigate the role of these Kupffer cells in the liver regeneration after partial hepatectomy (PHx) in mice. The proportion of Kupffer cell subsets in the remnant liver was examined in C57BL/6 mice by flow cytometry after PHx. To examine the role of CD11b+Kupffer cells/Mφ, mice were depleted of these cells before PHx by non-lethal 5 Gy irradiation with or without bone marrow transplantation (BMT) or the injection of a CCR2 (MCP-1 receptor) antagonist, and liver regeneration was evaluated. Although the proportion of CD68+Kupffer cells did not significantly change after PHx, the proportion of CD11b+Kupffer cells/Mφ and their FasL expression was greatly increased at three days after PHx, when the hepatocytes vigorously proliferate. Serum TNF and MCP-1 levels peaked one day after PHx. Irradiation eliminated the CD11b+Kupffer cells/Mφ for approximately two weeks in the liver, while CD68+Kupffer cells, NK cells and NKT cells remained, and hepatocyte regeneration was retarded. However, BMT partially restored CD11b+Kupffer cells/Mφ and recovered the liver regeneration. Furthermore, CCR2 antagonist treatment decreased the CD11b+Kupffer cells/Mφ and significantly inhibited liver regeneration. The CD11b+Kupffer cells/Mφ recruited from bone marrow by the MCP-1 produced by CD68+Kupffer cells play a pivotal role in liver regeneration via the TNF/FasL/Fas pathway after PHx.
| S-EPMC4557907 | biostudies-literature
Project description:We have recently reported that Kupffer cells consist of two subsets, radio-resistant resident CD68+ Kupffer cells and radio-sensitive recruited CD11b+ Kupffer cells/macrophages (M?s). Non-alcoholic steatohepatitis (NASH) is characterized not only by hepatic steatosis but also chronic inflammation and fibrosis. In the present study, we investigated the immunological mechanism of diet-induced steatohepatitis in fibroblast growth factor 5 (FGF5) deficient mice. After consumption of a high fat diet (HFD) for 8 weeks, FGF5 null mice developed severe steatohepatitis and fibrosis resembling human NASH. F4/80+ M?s which were both CD11b and CD68 positive accumulated in the liver. The production of TNF and FasL indicated that they are the pivotal effectors in this hepatitis. The weak phagocytic activity and lack of CRIg mRNA suggested that they were recruited M?s. Intermittent exposure to 1 Gy irradiation markedly decreased these M?s and dramatically inhibited liver inflammation without attenuating steatosis. However, depletion of the resident subset by clodronate liposome (c-lipo) treatment increased the M?s and tended to exacerbate disease progression. Recruited CD11b+ CD68+ Kupffer cells/M?s may play an essential role in steatohepatitis and fibrosis in FGF5 null mice fed with a HFD. Recruitment and activation of bone marrow derived M?s is the key factor to develop steatohepatitis from simple steatosis.
| S-EPMC5052649 | biostudies-literature
Project description:Macrophages play central roles in inflammatory reactions and initiation of immune responses during infections. More than 80% of total tissue macrophages are described to be located in the liver as liver-resident macrophages, also named Kupffer cells (KCs). While studies in mice have established a central role of liver-resident KCs in regulating liver inflammation, their phenotype and function are not well-characterized in humans. Comparing paired human liver and peripheral blood samples, we observed significant differences in the distribution of macrophage (Mφ) subsets, with lower frequencies of CD14hiCD16lo and higher frequencies of CD14int-hiCD16int Mφ in human livers. Intrahepatic Mφ consisted of diverse subsets with differential expression of CD49a, a liver-residency marker previously described for human and mice NK cells, and VSIG4 and/or MARCO, two recently described human tissue Mφ markers. Furthermore, intrahepatic CD49a+ Mφ expressed significantly higher levels of maturation and activation markers, exhibited higher baseline levels of TNF-α, IL-12, and IL-10 production, but responded less to additional in vitro TLR stimulation. In contrast, intrahepatic CD49a- Mφ were highly responsive to stimulation with TLR ligands, similar to what was observed for CD49a- monocytes (MOs) in peripheral blood. Taken together, these studies identified populations of CD49a+, VSIG4+, and/or MARCO+ Mφ in human livers, and demonstrated that intrahepatic CD49a+ Mφ differed in phenotype and function from intrahepatic CD49a- Mφ as well as from peripheral blood-derived monocytes.
| S-EPMC6568245 | biostudies-literature