Resident Kupffer cell maladaptation in Liver Fibrosis is Rescued by Monocyte-Derived Syncytia of Macrophages
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ABSTRACT:
PROVIDER: PRJNA942300 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR23750108.fastq.gz | Fastqsanger.gz | |||
| SRR23750109.fastq.gz | Fastqsanger.gz | |||
| SRR23750110.fastq.gz | Fastqsanger.gz | |||
| SRR23750111.fastq.gz | Fastqsanger.gz | |||
| SRR23750112.fastq.gz | Fastqsanger.gz |
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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.
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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: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.
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Project description:Kupffer cells were sorted from the liver of WT mice and Atg5-specific deficient Kupffer cells mice. RNAs were extracted from the Kupffer cells and we performed an RNA-seq on these cells.
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Project description:Ulcerative colitis impact on Kupffer cell homeostasis was assessed using transcriptional analysis. Kupffer cells were sorted from the livers of mice treated with dextran sodium sulphate for 7 days. Total RNA preparation was performed on 20,000 sorted Kupffer cells.
2026-09-02 | E-MTAB-15568 | biostudies-arrayexpress
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.
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Project description:Kupffer cells (KCs) are the tissue resident macrophage population of the liver. With this experiment, we sought to investigate the potential consequences of decreasing embryonically-derived KC numbers on liver gene expression in the context of hypercholesterolemia. 3-month-old CD207-DTR x LDL-receptor deficient (C57BL6J background) female mice were injected with diphtheria toxin (DT) or heat-inactivated DT. Mice were then fed a cholesterol-rich diet to induce hypercholesterolemia. RNA sequencing was performed on liver RNA samples after 4 weeks of diet.
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Project description:The innate immune system functions as the first line of defense against cancer cells, particularly the detection and clearance of cancer cells by phagocytosis. The liver resident macrophages, known as Kupffer cells, have the largest population of body’s tissue resident macrophages and constitute the first line of defense against cancer cells invading the liver. However, the molecule mechanisms underlying the detection and phagocytosis of cancer cells by Kupffer cells are still unclear. Here, using in vivo genome-wide CRISPR-Cas9 knockout screening, we found that Ermap expressed on cancer cells delivered the pro-phagocytosis ‘eat me’ signal to promote Kupffer cells phagocytosis and control over liver metastasis of various cancer cells. Ermap ligated Galectin-9 expressed on Kupffer cells surface in a glycosylation dependent manner. Galectin-9 further formed a bridging complex with Ermap and transmembrane receptor Dectin-2 expressed on Kupffer cells to promote the detection and phagocytosis of cancer cells by Kupffer cells. Patients with tumors expressing low ERMAP had more liver metastases. Thus, our study identifies the Ermap–Galectin-9–Dectin-2 axis as an ‘eat me’ signal for Kupffer cells to engulf cancer cells and control liver metastasis.
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Project description:Tissue environment plays a powerful role in establishing and maintaining the distinct phenotypes of resident macrophages, but the underlying molecular mechanisms remain poorly understood. Here, we characterized transcriptomic and epigenetic changes in repopulating liver macrophages following acute Kupffer cell depletion as a means to infer signaling pathways and transcription factors that promote Kupffer cell differentiation. We obtain evidence that combinatorial interactions of the Notch ligand DLL4 and transforming growth factor-b (TGF-β) family ligands produced by sinusoidal endothelial cells and endogenous LXR ligands were required for the induction and maintenance of Kupffer cell identity. DLL4 regulation of the Notch transcriptional effector RBPJ activated poised enhancers to rapidly induce LXRα and other Kupffer cell lineage-determining factors. These factors in turn reprogrammed the repopulating liver macrophage enhancer landscape to converge on that of the original resident Kupffer cells. Collectively, these findings provide a framework for understanding how macrophage progenitor cells acquire tissue-specific phenotypes.
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