Liver macrophages in healthy and diseased liver (original) (raw)
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Harnessing metabolism of hepatic macrophages to aid liver regeneration
Cell Death & Disease
Liver regeneration is a dynamic and regulated process that involves inflammation, granulation, and tissue remodeling. Hepatic macrophages, abundantly distributed in the liver, are essential components that actively participate in each step to orchestrate liver regeneration. In the homeostatic liver, resident macrophages (Kupffer cells) acquire a tolerogenic phenotype and contribute to immunological tolerance. Following toxicity-induced damage or physical resection, Kupffer cells as well as monocyte-derived macrophages can be activated and promote an inflammatory process that supports the survival and activation of hepatic myofibroblasts and thus promotes scar tissue formation. Subsequently, these macrophages, in turn, exhibit the anti-inflammatory effects critical to extracellular matrix remodeling during the resolution stage. However, continuous damage-induced chronic inflammation generally leads to hepatic macrophage dysfunction, which exacerbates hepatocellular injury and trigger...
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...
Blood, 2007
Kupffer cells form a large intravascular macrophage bed in the liver sinusoids. The differentiation history and diversity of Kupffer cells is disputed; some studies argue that they are derived from blood monocytes, whereas others support a local origin from intrahepatic precursor cells. In the present study, we used both flow cytometry and immunohistochemistry to distinguish 2 subsets of Kupffer cells that were revealed in the context both of bone marrow transplantation and of orthotopic liver transplantation. One subset was radiosensitive and rapidly replaced from hematogenous precursors, whereas the other was relatively radioresistant and long-lived. Both were phagocytic but only the former population was recruited into inflammatory foci in response to CD8+ T-cell activation. We propose the name “sessile” for the radioresistant Kupffer cells that do not participate in immunoinflammatory reactions. However, we found no evidence that these sessile Kupffer cells arise from immature i...
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.
Immunity, 2019
Macrophages are strongly adapted to their tissue of residence. Yet, little is known about the cell-cell interactions that imprint the tissue-specific identities of macrophages in their respective niches. Using conditional depletion of liver Kupffer cells, we traced the developmental stages of monocytes differentiating into Kupffer cells and mapped the cellular interactions imprinting the Kupffer cell identity. Kupffer cell loss induced tumor necrosis factor (TNF)-and interleukin-1 (IL-1) receptor-dependent activation of stellate cells and endothelial cells, resulting in the transient production of chemokines and adhesion molecules orchestrating monocyte engraftment. Engrafted circulating monocytes transmigrated into the perisinusoidal space and acquired the liver-associated transcription factors inhibitor of DNA 3 (ID3) and liver X receptor-a (LXR-a). Coordinated interactions with hepatocytes induced ID3 expression, whereas endothelial cells and stellate cells induced LXR-a via a synergistic NOTCH-BMP pathway. This study shows that the Kupffer cell niche is composed of stellate cells, hepatocytes, and endothelial cells that together imprint the liver-specific macrophage identity.
Invading macrophages play a major role in the liver progenitor cell response to chronic liver injury
Journal of Hepatology, 2010
Background & Aims: Although a strong association between liver progenitor cells (LPCs) and inflammation exists in many chronic liver diseases, the exact role of the immune system in LPC-mediated hepatic regeneration remains unclear. A number of pro-inflammatory factors were identified in cytokine knockout mice in which the LPC response was attenuated but neither the mechanism nor the producing cells are known. Methods: To identify the critical immune cells and cytokines required in the LPC response, we compared two diet-induced models of liver injury with two recently established transgenic models of immune-mediated hepatitis. Results: Despite severe inflammation being observed in all models, the generation of LPCs was highly dependent on the cause and kinetics of liver damage. The LPC response was associated with an increase of macrophages and CD8 + T cells but not natural killer cells. T cell-deficient mice were able to mount a LPC response, albeit delayed, suggesting that T cells are not essential. Mice mounting an LPC response showed elevated numbers of Kupffer cells and invading CX 3 CR1 high CCR2 high macrophages secreting persistent high levels of tumour necrosis factor alpha (TNFa), a major cytokine involved in the LPC response. Conclusions: Liver macrophages are an important determinant of LPC expansion during liver regeneration in models of diet-and immune-mediated liver injury. Invading macrophages in particu-lar provide pro-mitogenic cytokines such as TNFa that underpin the process. LPC themselves are a source of chemokines (CCL2, CX 3 CL1) that attract infiltrating macrophages. Ó
Manuscript NAFLD hepatic macrophages fullwithdiagrams
How do we apply advances in knowledge of Hepatic Macrophages in treating Liver Diseases especially non alcoholic fatty liver disease( NAFLD), non alcoholic steatohepapititis( NASH), with the increasing incidence of Dibesity-A Systematic Review’’, 2020
With the increasing incidence of obesity and comorbidities like T2DMor Diabesity aswell as NAFLD and increasing numbers of liver transplantation there is an urgent need for finding answers for treating these.Earlier we have reviewed role of probiotics in obesity,NAFLD,withlevocarnitine(LC),nicotinamide riboside(NR) ,bile acid inhibitor (volixibat). Here we have further explored the role of macrophages with regards to liver homeostasis. Hepatic macrophages are basically constituted of Kupffer cells or circulating bone marrow(BM) derived monocytes .KC's are self renewable and don't migrate and are located in the liver sinusoids as compared to macrophages taking origin from circulating monocytes .KC'scontrol liver homeostasis by producing immunity against non-pathogenic blood borne molecules,while taking part in coordinated immune actions resulting in clearing of pathogens ,recruitment of leukocytes as well as antigen presentation to lymphocytes that reside in the vasculature .Monocyte derived macrophages(Mo MF's) infiltrate within liver tissues if metabolic or toxic injury occurs and probably can be dispensed with by replacing macrophages in homeostasis .Recently various Hepatic macrophages populations have been earmarked having separate phenotypes with special functions much further than the classically M1 ,M2 segregation. Hepatic macrophages have a special part in pathogenesis of acute as well as chronic liver disease, alcoholic liver disease(ALD); non alcoholic fatty liver disease(NAFLD), non alcoholic steatohepapititis;(NASH),hepatocellular carcinoma(HCC)and in resolution of liver diseases .This insight of Hepatic macrophages populations help in formatting targeted therapies .Here we review the details of therapeutics designed and are under trial on these basis.