Albumin treatment transcriptionally reprograms circulating immune cells in patients with acutely decompensated cirrhosis
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ABSTRACT:
PROVIDER: PRJNA720693 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
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| SRR14192519_1.fastq.gz | Fastqsanger.gz | |||
| SRR14192519_2.fastq.gz | Fastqsanger.gz | |||
| SRR14192520_1.fastq.gz | Fastqsanger.gz | |||
| SRR14192520_2.fastq.gz | Fastqsanger.gz | |||
| SRR14192521_1.fastq.gz | Fastqsanger.gz |
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Project description:BACKGROUND AND AIMS: The effects of intravenous albumin on lymphocyte perturbations and defective neutrophil anti-microbial functions that characterize patients with acute-on-chronic liver failure (ACLF) are unknown. METHODS: Forty-nine patients admitted for severe acutely decompensated cirrhosis without ACLF were investigated with the use of whole-blood RNA sequencing (RNA-seq) on admission and after a median period of 15 days once they had developed ACLF. Such patients were selected because they follow a steady systemic inflammation course. Thirty patients had received albumin during the progression to ACLF but not the 19 others. Single-cell RNA-seq (scRNA-seq) in peripheral blood mononuclear cells (PBMCs) exposed ex vivo to albumin or vehicle for 2 hours, and assessment of the anti-microbial capacity of neutrophils exposed ex vivo to albumin were performed in additional patients with acutely decompensated cirrhosis. RESULTS: Analysis of whole-blood RNA-seq data revealed that patients who had received albumin exhibited specific upregulation of signatures related to B cells, plasma cells and immunoglobulins; CD4 T cells; myeloid cells; mismatch repair, cell cycle and mitosis; and transcription factors such as c-Myc and E2F family members. The use of scRNA-seq to analyze patients' PBMCs exposed ex vivo to albumin showed increases in signatures related to B cells, myeloid cells, and CD4 T cells. Neutrophils exposed ex vivo to albumin exhibited increased chemotactic and degranulation responses, enhanced phagocytosis, and increased pathogen-destroying swarming functions. CONCLUSIONS: In patients with severe acutely decompensated cirrhosis, albumin rewires transcription in B cells, CD4 T cells and mononuclear myeloid cells, and resets neutrophil anti-microbial functions to normal.
2025-04-08 | GSE171741 | GEO
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
Project description: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.
2020-03-24 | GSE124878 | GEO
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
Project description:Peritoneal macrophage heterogeneity in decompensated liver cirrhosis
| PRJNA514059 | ENA
Project description:MOLECULAR PROFILING OF DECOMPENSATED CIRRHOSIS BY A NOVEL microRNA SIGNATURE
| PRJNA633887 | ENA
Project description:Microarray of PBMC from patients with decompensated cirrhosis (AD) and ACLF stimulated with CpG-DNA and treated with human serum albumin (HSA)
| PRJNA610612 | ENA
Project description:Liver disease is one of the leading causes of death worldwide. Patients with cirrhosis display an increased predisposition to and mortality from infection due to multimodal defects in the innate immune system; however, the causative mechanism has remained elusive. We present evidence that the cyclooxygenase (COX)-derived eicosanoid prostaglandin E2 (PGE2) drives cirrhosis-associated immunosuppression. We observed elevated circulating concentrations (more than seven times as high as in healthy volunteers) of PGE2 in patients with acute decompensation of cirrhosis. Plasma from these and patients with end-stage liver disease (ESLD) suppressed macrophage proinflammatory cytokine secretion and bacterial killing in vitro in a PGE2-dependent manner via the prostanoid type E receptor-2 (EP2), effects not seen with plasma from patients with stable cirrhosis (Child-Pugh score grade A). Albumin, which reduces PGE2 bioavailability, was decreased in the serum of patients with acute decompensation or ESLD (<30 mg/dl) and appears to have a role in modulating PGE2-mediated immune dysfunction. In vivo administration of human albumin solution to these patients significantly improved the plasma-induced impairment of macrophage proinflammatory cytokine production in vitro. Two mouse models of liver injury (bile duct ligation and carbon tetrachloride) also exhibited elevated PGE2, reduced circulating albumin concentrations and EP2-mediated immunosuppression. Treatment with COX inhibitors or albumin restored immune competence and survival following infection with group B Streptococcus. Taken together, human albumin solution infusions may be used to reduce circulating PGE2 levels, attenuating immune suppression and reducing the risk of infection in patients with acutely decompensated cirrhosis or ESLD.
| S-EPMC5369639 | biostudies-literature
Project description:The pathophysiological background of decompensated cirrhosis is characterised by a systemic proinflammatory and pro-oxidant milieu that plays a major role in the development of multiorgan dysfunction. Such abnormality is mainly due to the systemic spread of bacteria and/or bacterial products from the gut and danger-associated molecular patterns from the diseased liver triggering the release of proinflammatory mediators by activating immune cells. The exacerbation of these processes underlies the development of acute-on-chronic liver failure. A further mechanism promoting multiorgan dysfunction and failure likely consists with a mitochondrial oxidative phosphorylation dysfunction responsible for systemic cellular energy crisis. The systemic proinflammatory and pro-oxidant state of patients with decompensated cirrhosis is also responsible for structural and functional changes in the albumin molecule, which spoil its pleiotropic non-oncotic properties such as antioxidant, scavenging, immune-modulating and endothelium protective functions. The knowledge of these abnormalities provides novel targets for mechanistic treatments. In this respect, the oncotic and non-oncotic properties of albumin make it a potential multitarget agent. This would expand the well-established indications to the use of albumin in decompensated cirrhosis, which mainly aim at improving effective volaemia or preventing its deterioration. Evidence has been recently provided that long-term albumin administration to patients with cirrhosis and ascites improves survival, prevents complications, eases the management of ascites and reduces hospitalisations. However, variant results indicate that further investigations are needed, aiming at confirming the beneficial effects of albumin, clarifying its optimal dosage and administration schedule and identify patients who would benefit most from long-term albumin administration.
| S-EPMC7282556 | biostudies-literature
Project description:Decompensated liver cirrhosis has a dismal prognosis, with patients surviving on average for 2-4 years after the first diagnosis of ascites. Albumin is an important tool in the therapy of cirrhotic ascites. By virtue of its oncotic properties, it reduces the risk of cardiovascular dysfunction after paracentesis. Treatment with albumin also counteracts the development of hepatorenal syndrome and spontaneous bacterial peritonitis. More recently, the positive impact of long-term albumin supplementation in liver disease, based on its pleiotropic non-oncotic activities, has been recognized. These include transport of endo- and exogenous substances, anti-inflammatory, antioxidant and immunomodulatory activities, and stabilizing effects on the endothelium. Besides the growing recognition that effective albumin therapy requires adjustment of the plasma level to normal physiological values, the search for substances with adjuvant activities is becoming increasingly important. More than 75% of patients with decompensated liver cirrhosis do not only present with hypoalbuminemia but also with zinc deficiency. There is a close relationship between albumin and the essential trace element zinc. First and foremost, albumin is the main carrier of zinc in plasma, and is hence critical for systemic distribution of zinc. In this review, we discuss important functions of albumin in the context of metabolic, immunological, oxidative, transport, and distribution processes, alongside crucial functions and effects of zinc and their mutual dependencies. In particular, we focus on the major role of chronic inflammatory processes in pathogenesis and progression of liver cirrhosis and how albumin therapy and zinc supplementation may affect these processes.
| S-EPMC8618355 | biostudies-literature