Kupffer cell heterogeneity: functional properties of bone marrow–derived and sessile hepatic macrophages (original) (raw)
Related papers
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.
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 (
Liver macrophages in healthy and diseased liver
Pflugers Archiv : European journal of physiology, 2017
Kupffer cells, the largest tissue resident macrophage population, are key for the maintenance of liver integrity and its restoration after injury and infections, as well as the local initiation and resolution of innate and adaptive immunity. These important roles of Kupffer cells were recently identified in healthy and diseased liver revealing diverse functions and phenotypes of hepatic macrophages. High-level phenotypic and genomic analysis revealed that Kupffer cells are not a homogenous population and that the hepatic microenvironment actively shapes both phenotype and function of liver macrophages. Compared to macrophages from other organs, hepatic macrophages bear unique properties that are instrumental for their diverse roles in local immunity as well as liver regeneration. The diverse and, in part, contradictory roles of hepatic macrophages in anti-tumor and inflammatory immune responses as well as regulatory and regenerative processes have been obscured by the lack of approp...
Journal of Hepatology, 2016
Background & Aims: Kupffer cells (KCs), the resident tissue macrophages of the liver, play a crucial role in the clearance of pathogens and other particulate materials that reach the systemic circulation. Recent studies have identified KCs as a yolk sac-derived resident macrophage population that is replenished independently of monocytes in the steady state. Although it is now established that following local tissue injury, bone marrow derived monocytes may infiltrate the tissue and differentiate into macrophages, the extent to which newly differentiated macrophages functionally resemble the KCs they have replaced has not been extensively studied. Methods: We studied the two populations of KCs using intravital microscopy, morphometric analysis and gene expression profiling. An ion homeostasis gene signature, including genes associated with scavenger receptor function and extracellular matrix deposition, allowed discrimination between these two KC sub-types. Results: Bone marrow derived ''KCs" accumulating as a result of genotoxic injury, resemble but are not identical to their yolk sac counterparts. Reflecting the differential expression of scavenger receptors, yolk sac-derived KCs were more effective at accumulating acetylated low density lipoprotein, whereas surprisingly, they were poorer than bone marrow-derived KCs when assessed for uptake of a range of bacterial pathogens. The two KC populations were almost indistinguishable in regard to i) response to lipopolysaccharide challenge, ii) phagocytosis of effete red blood cells and iii) their ability to contain infection and direct granuloma formation against Leishmania donovani, a KC-tropic intracellular parasite. Conclusions: Bone marrow-derived KCs differentiate locally to resemble yolk sac-derived KC in most but not all respects, with implications for models of infectious diseases, liver injury and bone marrow transplantation. In addition, the gene signature we describe adds to the tools available for distinguishing KC subpopulations based on their ontology. Lay summary: Liver macrophages play a major role in the control of infections in the liver and in the pathology associated with chronic liver diseases. It was recently shown that liver macrophages can have two different origins, however, the extent to which these populations are functionally distinct remains to be fully addressed. Our study demonstrates that whilst liver macrophages share many features in common, regardless of their origin, some subtle differences in function exist. Data repository: Gene expression data are available from the European Bioinformatics Institute ArrayExpress data repository (accession number E-MTAB-4954).
Frontiers in Immunology
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...
Liver inflammation abrogates immunological tolerance induced by Kupffer cells
Hepatology (Baltimore, Md.), 2015
The liver is essential for inducing immunological tolerance towards harmless antigens to maintain immune system homeostasis. However, the precise cellular mechanisms of tolerance induction against particle-bound antigens, the role of the local hepatic microenvironment and implications for therapeutic targets in immune-mediated diseases are currently unclear. In order to elucidate cellular mechanisms of tolerance induction in healthy and injured liver, we developed a novel in vivo system combining the systemic delivery of low-dose peptide antigens coupled to inert particles, immunological read-outs and sophisticated intravital multiphoton microscopy based imaging of the liver in mice. We show that liver resident macrophages, Kupffer cells (KC), but not hepatic monocyte-derived macrophages or dendritic cells (DC), are the central cellular scavenger for circulating particle-associated antigens in homeostasis. KC-associated antigen presentation induces CD4 T cell arrest, expansion of na...
The American journal of pathology, 2016
Kupffer cells (KC) play major roles in immunity and tissue injury or repair. Because recapitulation of KC biology and function within liver will allow superior insights into their functional repertoire, we studied the efficacy of the cell transplantation approach for this purpose. Mouse KC were isolated from donor livers, characterized, and transplanted into syngeneic recipients. To promote cell engraftment through impairments in native KC, recipients were preconditioned with gadolinium chloride. The targeting, fate, and functionality of transplanted cells were evaluated. The findings indicated that transplanted KC engrafted and survived in recipient livers throughout the study period of 3 months. Transplanted KC expressed macrophage functions, including phagocytosis and cytokine expression, with or without genetic modifications using lentiviral vectors. This permitted studies of whether transplanted KC could affect outcomes in the context of acetaminophen hepatotoxicity or hepatic ...
Journal of leukocyte biology, 1986
The relative significance of local proliferation and extrahepatic recruitment of Kupffer cells was investigated by partial-body irradiation before the induction of macrophage hyperplasia by zymosan. There was no difference in growth of the Kupffer cells population between nonirradiated rats and rats irradiated with the liver shielded, whereas irradiation of the liver with the rest of the body (bone marrow) shielded resulted in strong inhibition of growth (-61%). Splenectomy combined with bone marrow irradiation inhibited growth to a lesser extent as compared to liver irradiation (-38%). Monocyte and other leukocyte numbers were strongly reduced in peripheral blood and their accumulation in the liver was completely prevented by bone marrow irradiation. Our results demonstrate that local proliferation of resident Kupffer cells represents the predominant source for their increased number during hyperplasia.