Resident Kupffer cell maladaptation in Liver Fibrosis is Rescued by Monocyte-Derived Syncytia of Macrophages
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PROVIDER: PRJNA942300 | ENA |
REPOSITORIES: ENA
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Project description:To investigate the effects of liver fobrosis and alteration in liver architecture in the regulation of embryonic Kupffer cells identity and funtion, we used a well stablished carbon tetrachloride model to induce liver fibrosis.
2024-03-08 | GSE226946 | GEO
Project description:Molecular profiling of infiltrating monocyte-derived macrophages versus resident kupffer cells following acute liver injury The liver has a remarkable capacity to regenerate after injury; yet, the role of macrophages (MF) in this process remains controversial mainly due to difficulties in distinguishing between different MF-subsets. Here, we utilized a murine model of acute liver injury caused by overdose of acetaminophen (APAP) and defined three distinct MF subsets that populate the liver following injury. Accordingly, resident Kupffer cells (KC) were significantly reduced upon APAP-challenge and started recovering by self-renewal at resolution phase without contribution of circulating Ly6Chi monocytes. The latter were recruited in a CCR2 and M-CSF mediated pathway at the necro-inflammatory phase and differentiated into ephemeral Ly6Clo MF subset at resolution phase. Moreover, their inducible ablation resulted in impaired recovery. Microarray based molecular profiling uncovered high similarity between steady state KC and those recovered at the resolution phase. In contrast, KC and monocyte-derived MF displayed distinct pro-restorative genetic signature at the resolution phase. Finally, we show that infiltrating monocytes acquire a pro-restorative polarization manifested by unique expression of pro-angiogenesis mediators and genes involved with inhibition of neutrophil activity and recruitment and promotion of their clearance. Collectively, our results present a novel phenotypic, ontogenic and molecular definition of liver-MF compartment following acute injury. 11 Samples (arrays) were performed. We generated pairwise comparison between all the different macrophages stages, using Partek Genomics Suite. Genes with p?5%[FDR] and a fold-change difference of ?2 or <-2 were selected.
2014-08-01 | E-GEOD-55606 | biostudies-arrayexpress
Project description:Molecular profiling of infiltrating monocyte-derived macrophages versus resident kupffer cells following acute liver injury The liver has a remarkable capacity to regenerate after injury; yet, the role of macrophages (MF) in this process remains controversial mainly due to difficulties in distinguishing between different MF-subsets. Here, we utilized a murine model of acute liver injury caused by overdose of acetaminophen (APAP) and defined three distinct MF subsets that populate the liver following injury. Accordingly, resident Kupffer cells (KC) were significantly reduced upon APAP-challenge and started recovering by self-renewal at resolution phase without contribution of circulating Ly6Chi monocytes. The latter were recruited in a CCR2 and M-CSF mediated pathway at the necro-inflammatory phase and differentiated into ephemeral Ly6Clo MF subset at resolution phase. Moreover, their inducible ablation resulted in impaired recovery. Microarray based molecular profiling uncovered high similarity between steady state KC and those recovered at the resolution phase. In contrast, KC and monocyte-derived MF displayed distinct pro-restorative genetic signature at the resolution phase. Finally, we show that infiltrating monocytes acquire a pro-restorative polarization manifested by unique expression of pro-angiogenesis mediators and genes involved with inhibition of neutrophil activity and recruitment and promotion of their clearance. Collectively, our results present a novel phenotypic, ontogenic and molecular definition of liver-MF compartment following acute injury.
2014-08-01 | GSE55606 | GEO
Project description:Kupffer cells (KCs) are the largest tissue resident macrophage population in direct contact with blood and thus with circulating lipoproteins. How KCs homeostasis is affected by the build-up of cholesterol-rich lipoproteins in the context of hypercholesterolemia has been poorly investigated. In this study, 5-month-old LDL receptor deficient (C57BL6J background) male mice were subjected to chow diet or a cholesterol-rich (HC) diet for four days to induce hypercholesterolemia. RNA sequencing was then performed on cell sorted KCs.
2024-09-05 | E-MTAB-12611 | biostudies-arrayexpress
Project description:Self-renewing tissue-resident macrophages are thought to be exclusively derived from embryonic progenitors. However, whether circulating monocytes can also give rise to such macrophages has not been formally investigated. Here we use a new model of diphtheria toxin-mediated depletion of liver-resident Kupffer cells to generate niche availability and show that circulating monocytes engrafted in the liver, gradually adopt the transcriptional profile of their depleted counterparts and become long-lived self-renewing cells. Underlining the physiological relevance of our findings, circulating monocytes also contribute to the expanding pool of macrophages in the liver shortly after birth, when macrophage niches become available during normal organ growth. Thus, like embryonic precursors, monocytes can and do give rise to self-renewing tissue-resident macrophages if the niche is available to them. Clec4F+ Kupffer cells were isolated and sorted from livers from adult WT mice or KC-DTR or KC-DTR littermate control mice +/- 50ng DT at indicated timepoints. 19 samples (arrays) in total. RNA was isolated, amplified with Nugene pico kit, converted to cDNA and then hybridised on Affymetrix GeneChip Mouse Gene 1.0 ST Arrays.
2015-11-21 | E-GEOD-75225 | biostudies-arrayexpress
Project description:Immunotherapy is revolutionizing cancer treatment but can trigger toxicities that remain poorly understood. Here, by comprehensively analyzing mouse models following anti-CD40 therapy, we found an interdependent induction of the cytokines IFN-g and IL-12, which caused inflammatory pathology in various tumor-free tissues. In the liver, Kupffer cells mediated toxicity by sensing lymphocyte-derived IFN-g and producing IL-12, highlighting the vulnerability of tissue-resident macrophages to promote toxicity when reacting to proinflammatory cues. Conversely, dendritic cells drove tumor control but were dispensable for toxicity. We further show that liver macrophages, IL-12, and IFN-g were not toxic themselves, but prompted a neutrophil response that determined the severity of tissue damage. Similar inflammatory pathways characterized immunotherapy-related adverse events in cancer patients. These findings implicate resident macrophages and neutrophils as mediators and effectors of aberrant inflammation, and suggest distinct cellular mechanisms of toxicity and antitumor immunity.
2021-06-03 | GSE175737 | GEO
Project description:Resident Kupffer cells and neutrophils drive liver toxicity in cancer immunotherapy
| PRJNA733462 | ENA
Project description:Resident Kupffer cells and neutrophils drive liver toxicity in cancer immunotherapy
| PRJNA734933 | ENA
Project description:Macrophage population in most mammalian organs consists of cells of different origin, with the exception of the central nervous system and the liver, where macrophages of monocytic origin are almost completely absent. The reasons for such distribution and the phenomenon of coexistence of the two separate macrophage lineages with different origin in mammals remain poorly understood. In present study we compared Kupffer cells and monocytes by the immunophenotype, gene expression profile, proteome and pool of mircoRNA. Observed differences do not allow to consider the resident liver macrophages as purely M2 macrophages or monocytes have purely M1 features. Two populations of macrophages of monocytic origin and resident macrophages have fundamentally different roles in maintaining homeostasis. Monocytic macrophages are involved in the regulation of inflammation, and resident macrophages are involved in the regulation of specific organ functions (nitrogen metabolism, complement system protein synthesis). However, if other indicators would be considered as markers of macrophage activity, it is worth noting that Kupffer cells possess some features of M2 macrophages. This is indicated by their expression profile of let-7b/c/d/e miRNAs, a high content of proteins associated with oxidative phosphorylation, as well as an increased level of synthesis of Arg1, IL10.
2021-09-09 | PXD018586 | Pride
Project description:Kupffer cells are the first line of defense in the liver against pathogens, yet several microbes successfully target the liver, bypass immune surveillance, and effectively develop in this tissue. Our current, albeit poor, understanding of Kupffer cell-pathogen interactions has been largely achieved through the study of primary cells, requiring isolation from a large numbers of animals. To facilitate the study of Kupffer cell biology, an immortalized rat Kupffer cell line, RKC1, was developed. We performed a comparative global proteomic analysis of RKC1 and primary rat Kupffer cells (PRKC) to characterize their respective responses to lipopolysaccharide (LPS)-mediated immune stimulation. We identified patent differences in the proteomic response profile of RKC1 and PRKC to LPS. We observed that PRKC upregulated more immune function pathways and exhibited marked changes in cellular morphology following stimulation. We consequently analyzed the cytoskeletal signaling pathways of these cells in light of the fact that macrophages are known to induce cytoskeletal changes in response to pathogens. Our findings suggest that Kupffer cells respond differently to inflammatory stimulus than do monocyte-derived macrophages, and such data may provide insight into how pathogens, such as the malaria parasite, may have evolved mechanisms of liver entry through Kupffer cells without detection.
2015-07-03 | PXD001247 | Pride