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Peritoneal macrophage heterogeneity in decompensated liver cirrhosis

ABSTRACT: Peritoneal macrophages (PM) are thought to regulate peritoneal inflammation and control bacterial infections in decompensated liver cirrhosis. The aim of this study was to characterize human PM heterogeneity. Employing CD206 surface expression, we identified subsets of human large (LPM) and small (SPM) PM, which differed in granularity and maturation states. FACS-sorted LPM from patients with decompensated cirrhosis revealed discrete transcriptome clusters, comprising more than 4000 differentially regulated genes involved in cell cycle, metabolism, and immune signaling.

ORGANISM(S): Homo sapiens

PROVIDER: GSE124878 | GEO | 2020/03/24

REPOSITORIES: GEO

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Peritoneal macrophage heterogeneity in decompensated liver cirrhosis

Project description:Peritoneal macrophage heterogeneity in decompensated liver cirrhosis

| PRJNA514059 | ENA

MOLECULAR PROFILING OF DECOMPENSATED CIRRHOSIS BY A NOVEL microRNA SIGNATURE

Project description:Objectives Non-invasive staging of decompensated cirrhosis is an unmeet clinical need. The aims of this study were to characterize and validate a novel miRNA signature to stage decompensated cirrhosis and predict the portal pressure and cardiac dysfunction response to non-selective beta-blockers (NSBB). Design Serum samples from patients with decompensated cirrhosis (n=36) and healthy controls (n=36) were tested for a novel signature of five miRNAs (miR-452-5p, miR-429, miR-885-5p, miR-181b-5p, and miR-122-5p) identified in the secretome of primary human hepatocytes, and three miRNAs (miR-192-5p, miR-34a-5p and miR-29a-5p) previously discovered as biomarkers of chronic liver disease. All patients had ascites, that was refractory in 18 (50%), and were placed on NSBB for variceal bleeding prophylaxis. In all patients, serum miRNAs, hepatic venous pressure gradient (HVPG), and echocardiogram study was performed before and 1 month after NSBB. Results Cirrhotic patients had lower serum levels of miR-429, miR-885-5p, miR-181b-5p, miR-122-5p, miR-192-5p and miR-29a-5p (p<0.05). miR-452-5p and miR-429 expression were lower in NSBB responders (p=0.006). miR-181b-5p expression was greater in refractory- than in diuretic sensitive ascites (p=0.008) and correlated with serum creatinine. miR-452-5p and miR-885-5p were inversely correlated with baseline systemic vascular resistance (ρ=-0.46 p=0.007; and ρ=-0.41 p=0.01 respectively), and with diminished systolic contractility in patients with refractory ascites after NSBB (ρ=-0.55 p=0.02; and ρ=-0.55 p=0.02, respectively). Conclusion Analysis of a miRNA signature in serum distinguishes patients with decompensated cirrhosis who show more severe systemic circulatory dysfunction and compromised systolic function after beta-blockade, and those more likely to benefit from NSBB.

2021-02-10 | GSE150867 | GEO

MOLECULAR PROFILING OF DECOMPENSATED CIRRHOSIS BY A NOVEL microRNA SIGNATURE

Project description:MOLECULAR PROFILING OF DECOMPENSATED CIRRHOSIS BY A NOVEL microRNA SIGNATURE

| PRJNA633887 | ENA

Microarray of PBMC from patients with decompensated cirrhosis (AD) and ACLF stimulated with CpG-DNA and treated with human serum albumin (HSA)

Project description:Human serum albumin (HSA) is an emerging treatment for preventing excessive systemic inflammation and organ failure(s) in patients with acutely decompensated (AD) cirrhosis. Here, we investigated the molecular mechanisms underlying the immunomodulatory properties of HSA. Administration of HSA to patients with AD cirrhosis with elevated circulating bacterial DNA (CpG-DNA) was associated with reduced plasma cytokine levels. In isolated leukocytes, HSA abolished CpG-DNA-induced cytokine expression and release independently of its oncotic and scavenging properties. Similar anti-inflammatory effects were observed with recombinant human albumin. HSA exerted widespread changes on the immune cell transcriptome, specifically in genes related to the endosomal compartment involved in cytosolic DNA sensing and type I interferon responses. Flow cytometry and confocal microscopy analyses revealed that HSA was taken up by leukocytes and internalized in vesicles positively stained with EEA1, a marker of early endosomes. Indeed, HSA and CpG-DNA colocalized in endosomes, the compartment where CpG-DNA binds to TLR9, its cognate receptor. Furthermore, HSA also inhibited poly-(I:C)- and LPS-induced IRF3 phosphorylation and TRIF-mediated responses, which are exclusive of endosomal TLR3 and TLR4 signaling, respectively. The immunomodulatory actions of HSA did not compromise leukocyte defensive mechanisms such as phagocytosis, efferocytosis and intracellular ROS production. The in vitro immunomodulatory effects of HSA were confirmed in vivo in analbuminemic humanized FcRn transgenic mice. In conclusion, these findings indicate that HSA internalizes in immune cells and modulates their responses through interaction with endosomal TLR signaling, thus providing a mechanism for the benefits of HSA infusions in patients with cirrhosis.

2023-03-02 | GSE146462 | GEO

Intestinal Mucosal Mitochondrial Oxidative Phosphorylation worsens with Cirrhosis Progression and is ameliorated with FMT

Project description:Intestinal barrier dysfunction, driven by increased oxidative phosphorylation (OXPHOS) activity that leads to tissue hypoxia, contributes to the progression of cirrhosis, particularly impacting the upper intestine. This study explores the interplay between intestinal OXPHOS, gut microbiota changes, and the effects of fecal microbiota transplant (FMT) in cirrhotic patients. We investigated 32 age-matched men across three groups: healthy controls, compensated cirrhosis, and decompensated cirrhosis. Each underwent endoscopy with duodenal and ascending colon biopsies. Subsequently, in a follow-up study, nine patients with hepatic encephalopathy, previously enrolled in a randomized controlled trial for FMT capsules, underwent repeat pre and post-FMT upper endoscopy. Our bioinformatics analysis highlighted a significant upregulation of nuclear-encoded OXPHOS genes in both intestinal regions of cirrhosis patients compared to controls, with further dysregulation in the decompensated group. We also observed a strong correlation between shifts in gut microbiota composition, Model for End-Stage Liver Disease (MELD) scores, and OXPHOS activity. Following FMT, patients displayed a significant reduction in OXPHOS gene expression in the duodenum, suggesting that FMT may restore intestinal barrier function and offer a therapeutic avenue to mitigate liver disease progression. The findings indicate that managing intestinal OXPHOS and microbiota through FMT could be relevant in modulating microbially-based therapies.

2024-12-26 | GSE285291 | GEO

CRIG identifies a novel population of highly phagocytic peritoneal macrophages associated with disease severity in patients with cirrhosis and ascites

Project description:Infections are an important cause of morbidity and mortality in patients with decompensated cirrhosis and ascites. Hypothesising that innate immune dysfunction contributes to susceptibility to infection, we assessed ascitic fluid macrophage phenotype and function. The expression of complement receptor of the immunoglobulin superfamily (CRIg) and CCR2 defined two phenotypically and functionally distinct peritoneal macrophage sub-populations. The proportion of CRIgHi macrophages differed between patients, and in the same patient over time, and a high proportion of CRIgHi macrophages was associated with reduced disease severity (Model for End Stage Liver Disease (MELD)) score. As compared to CRIgLow macrophages, CRIgHi macrophages were highly phagocytic and displayed enhanced antimicrobial effector activity. Transcriptional profiling by RNA Sequencing and comparison with human macrophage and murine peritoneal macrophage expression signatures highlighted similarities between CRIgHi cells, human macrophages and mouse F4/80Hi resident peritoneal macrophages, and between CRIgLow macrophages, human monocytes and mouse F4/80Low monocyte-derived peritoneal macrophages. These data suggest CRIgHi and CRIgLow macrophages may represent a tissue-resident population and a monocyte-derived population, respectively. In conclusion, ascites fluid macrophage subset distribution and phagocytic capacity is highly variable between patients with chronic liver disease. Regulating the numbers and/or functions of these macrophage populations could provide therapeutic opportunities in cirrhotic patients.

2017-08-22 | GSE79833 | GEO

Transcriptomic analysis of Kupffer cells in patients with cirrhosis

Project description:Background and aims: Patients with decompensated cirrhosis present serious infections of bacterial origin. During homeostasis, resident macrophages from the liver or Kupffer cells (KCS) play a key role in the phagocytosis of circulating bacteria. The objective of this study was to characterize the transcripomic and functional profile of KCs in liver cirrhosis and its relationship with the risk of infections. Methods: KCs were isolated from livers of patients with cirrhosis (n = 4) and controls (n = 5) and the profile was determined by RNA sequencing. The phenotype and altered molecular pathways of the isolated KCS were analyzed through GSEA . Results: The expression profile of KCs is specific and different depending on whether they reside in a cirrhotic or control liver. The GO analysis revealed that the pathways differentially expressed in KCs isolated from cirrhotic liver are implicated in the immune response. The GSEA showed that KCs isolated from patients with cirrhosis present a greater overexpression of M1 markers with respect to M2 (normalized enrichment score, NES: 1.68, p <0.01 vs. NES: 0.8, p <0.01). Conclusion: The KCS of patients with cirrhosis have a unique and distinct gene expression profile characterized by up-regulation of M1 markers.

2020-09-11 | GSE123661 | GEO

Rat hepatocytes: Advanced cirrhosis vs Control liver, Advanced cirrhosis vs Early cirrhosis

Project description:Gene profiling of hepatocytes in early and advanced cirrhotic Rats Two-condition experiment, Advanced cirrhosis vs Control liver, Advanced cirrhosis vs Early cirrhosis. Biological replicates: 5 Advanced cirrhosis, 5 Early cirrhosis, 5 control liver. Each hepatocyte was isolated independently. One replicate per array.

2011-11-02 | E-GEOD-22977 | biostudies-arrayexpress

Improvement of liver cirrhosis using hepatocyte-derived liver progenitor-like cells (HepLPCs): a prospective, open label, single arm, safety trial

Project description:The escalating demand for liver transplantation, coupled with the scarcity of donor organs and inherent transplantation risks, underscores the urgent need for innovative cirrhosis treatments. To address this, we have developed a protocol for transforming human primary hepatocytes into expandable Hepatocyte-Derived Liver Progenitor-Like Cells (HepLPCs). In animal models, these cells exhibited anti-fibrotic properties and facilitated liver regeneration. This study comprises a pre-clinical phase and an inaugural clinical trial involving nine cirrhosis patients to assess the feasibility and safety of HepLPC treatment. The HepLPCs infusion was well-tolerated, devoid of transfusion reactions or dose-limiting toxicities. Primary outcome measures, encompassing safety and feasibility, were successfully met. Notably, the results revealed enhanced liver function following HepLPCs infusion, indicating significant improvements in cirrhosis indicators over a 6-month observation period. These promising findings advocate for the therapeutic potential of HepLPCs as an innovative strategy for liver cirrhosis, warranting further exploration through clinical trials, particularly in decompensated cirrhosis and acute-on-chronic liver failure patients.

2024-12-30 | GSE248227 | GEO

Gene expression profile (RNAseq) of wild-type and Zeb1 (+/-) peritoneal mouse macrophages

Project description:Purpose: Characterize the gene expression profile of wild-type and Zeb1 (+/-) peritoneal mouse macrophages through RNA sequencing Methods: RNA sequencing of RNA from peritoneal macrophages isolated by peritoneal lavage and FACS sorting (F4/80+ CD11b+) from wild-type and Zeb1 (+/-) mice (2 mice pooled for each sample/set) Results: Wild-type and Zeb1 (+/-) peritoneal mouse macrophages display differential gene expression. Zeb1 (+/-) peritoneal macrophages express lower levels of SPM (F4/80low)-associated genes Conclusions: Wild-type and Zeb1 (+/-) peritoneal mouse macrophages display differential gene expression. Zeb1 (+/-) peritoneal macrophages express lower levels of SPM (F4/80low)-associated genes

2019-05-24 | GSE103830 | GEO

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