Inflammatory cytokines and organ dysfunction associate with the aberrant DNA methylome of monocytes in sepsis
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PROVIDER: PRJNA574451 | ENA |
REPOSITORIES: ENA
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Project description:BackgroundSepsis, a life-threatening organ dysfunction caused by a dysregulated systemic immune response to infection, associates with reduced responsiveness to subsequent infections. How such tolerance is acquired is not well understood but is known to involve epigenetic and transcriptional dysregulation.MethodsBead arrays were used to compare global DNA methylation changes in patients with sepsis, non-infectious systemic inflammatory response syndrome, and healthy controls. Bioinformatic analyses were performed to dissect functional reprogramming and signaling pathways related to the acquisition of these specific DNA methylation alterations. Finally, in vitro experiments using human monocytes were performed to test the induction of similar DNA methylation reprogramming.ResultsHere, we focused on DNA methylation changes associated with sepsis, given their potential role in stabilizing altered phenotypes. Tolerized monocytes from patients with sepsis display changes in their DNA methylomes with respect to those from healthy controls, affecting critical monocyte-related genes. DNA methylation profiles correlate with IL-10 and IL-6 levels, significantly increased in monocytes in sepsis, as well as with the Sequential Organ Failure Assessment score; the observed changes associate with TFs and pathways downstream to toll-like receptors and inflammatory cytokines. In fact, in vitro stimulation of toll-like receptors in monocytes results in similar gains and losses of methylation together with the acquisition of tolerance.ConclusionWe have identified a DNA methylation signature associated with sepsis that is downstream to the response of monocytes to inflammatory signals associated with the acquisition of a tolerized phenotype and organic dysfunction.
| S-EPMC6820973 | biostudies-literature
Project description:Genome wide DNA methylation profiling of monocytes from healthy donors, systemic inflammatory response syndrome (SIRS) and septic patients. The Illumina Infinium MethylationEPIC Beadchip was used to obtain DNA methylation profiles across approximately 850,000 CpGs in CD14+CD66bneg monocytes isolated from PBMCs of 11 healthy donors, 4 SIRS and 14 septic patients.
2019-10-03 | GSE138074 | GEO
Project description:Background: Sepsis involves aberrant immune responses to infection, but the exact nature of this immune dysfunction remains poorly defined. Bacterial endotoxins like lipopolysaccharide (LPS) are potent inducers of inflammation, which has been associated with the pathophysiology of sepsis, but repeated exposure can also induce a suppressive effect known as endotoxin tolerance or cellular reprogramming. It has been proposed that endotoxin tolerance might be associated with the immunosuppressive state that was primarily observed during late-stage sepsis. However, this relationship remains poorly characterised. Here we clarify the underlying mechanisms and timing of immune dysfunction in sepsis. Methods: We defined a gene expression signature characteristic of endotoxin tolerance. Gene-set test approaches were used to correlate this signature with early sepsis, both newly and retrospectively analysing microarrays from 593 patients in 11 cohorts. Then we recruited a unique cohort of possible sepsis patients at first clinical presentation in an independent blinded controlled observational study to determine whether this signature was associated with the development of confirmed sepsis and organ dysfunction. Findings: All sepsis patients presented an expression profile strongly associated with the endotoxin tolerance signature (p < 0.01; AUC 96.1%). Importantly, this signature further differentiated between suspected sepsis patients who did, or did not, go on to develop confirmed sepsis, and predicted the development of organ dysfunction. Interpretation: Our data support an updated model of sepsis pathogenesis in which endotoxin tolerance-mediated immune dysfunction (cellular reprogramming) is present throughout the clinical course of disease and related to disease severity. Thus endotoxin tolerance might offer new insights guiding the development of new therapies and diagnostics for early sepsis. For the RNA-Seq study reported here, 73 patients were recruited with deferred consent at the time of first examination in an emergency ward based on the opinion of physicians that there was a potential for the patient's condition to develop into sepsis. These were retrospectively divided into groups based on clinical features and compared to 11 non-urgent surgical controls.
2014-11-14 | E-GEOD-63311 | biostudies-arrayexpress
Project description:Background: Sepsis involves aberrant immune responses to infection, but the exact nature of this immune dysfunction remains poorly defined. Bacterial endotoxins like lipopolysaccharide (LPS) are potent inducers of inflammation, which has been associated with the pathophysiology of sepsis, but repeated exposure can also induce a suppressive effect known as endotoxin tolerance or cellular reprogramming. It has been proposed that endotoxin tolerance might be associated with the immunosuppressive state that was primarily observed during late-stage sepsis. However, this relationship remains poorly characterised. Here we clarify the underlying mechanisms and timing of immune dysfunction in sepsis. Methods: We defined a gene expression signature characteristic of endotoxin tolerance. Gene-set test approaches were used to correlate this signature with early sepsis, both newly and retrospectively analysing microarrays from 593 patients in 11 cohorts. Then we recruited a unique cohort of possible sepsis patients at first clinical presentation in an independent blinded controlled observational study to determine whether this signature was associated with the development of confirmed sepsis and organ dysfunction. Findings: All sepsis patients presented an expression profile strongly associated with the endotoxin tolerance signature (p < 0.01; AUC 96.1%). Importantly, this signature further differentiated between suspected sepsis patients who did, or did not, go on to develop confirmed sepsis, and predicted the development of organ dysfunction. Interpretation: Our data support an updated model of sepsis pathogenesis in which endotoxin tolerance-mediated immune dysfunction (cellular reprogramming) is present throughout the clinical course of disease and related to disease severity. Thus endotoxin tolerance might offer new insights guiding the development of new therapies and diagnostics for early sepsis.
2014-11-14 | GSE63311 | GEO
Project description:Endothelial dysfunction is a primary contributor to sepsis-related organ dysfunction and death. In sepsis animal models, endothelial progenitor cells (EPC) have contributed to vascular repair. The role of endothelial progenitor cells as a biomarker for organ dysfunction is still unknown. We hypothesized that circulating numbers of endothelial progenitor cells would be associated with improved outcomes in sepsis.Prospective, observational single-center cohort study in adult intensive care units at Grady Memorial Hospital, an affiliate of Emory University, from July 2007 through April 2009. Peripheral blood was obtained from 95 patients with sepsis, 37 intensive care unit controls, and 51 healthy controls, of whom only 86 patients with sepsis were used in the analysis because we were not able to obtain enough blood in 9 sepsis patients. Clinical data were obtained, and organ dysfunction was measured by Sepsis-Related Organ Failure Assessment (SOFA) score. Endothelial progenitor cells were assessed by a colony-forming unit (CFU) assay in which peripheral blood mononuclear cells were isolated using Ficoll density-gradient centrifugation and cultured in growth media.The patients with sepsis had significantly lower mean endothelial progenitor cell colony counts compared with intensive care unit controls (p = 0.035) and healthy controls (p = 0.0005). There was no difference in colony counts between ICU controls and healthy controls (p = 0.81). In the sepsis patients, EPC CFU numbers inversely associated with SOFA score, adjusting for mortality (r (2) = 0.05, p = 0.04).Increased circulating endothelial progenitor cells inversely correlate with organ dysfunction in sepsis patients.
| S-EPMC3749881 | biostudies-literature
Project description:Sepsis-induced multiple organ dysfunction syndrome (MODS) is a major cause of morbidity and mortality in critically ill patients and remains impervious to most therapeutic interventions. We utilized a clinically relevant murine model of MODS induced by ventilator-associated pneumonia to systematically delineate pathways dysregulated in lung, liver, and kidney. We focused on processes commonly activated across injured organs and constructed a MODS-associated network based on connectivity among the gene members of these functionally coherent pathways. Our analyses led to the identification of several putative drivers of MODS whose expression was regulated by epidermal growth factor receptor. Our unbiased, integrative method is a promising approach to unravel mechanisms in system-wide disorders afflicting multiple compartments such as sepsis-induced MODS, and guide the discovery of novel putative therapeutic targets.
2014-12-31 | GSE60088 | GEO
Project description:Despite decades of research, sepsis remains one of the most urgent unmet medical needs. Clinical trials in sepsis have mainly focused on targeting the inflammatory pathway, however, recent data indicate that sepsis should also be seen as a metabolic disease. Targeting metabolic dysregulations that take place in sepsis might uncover novel therapeutic opportunities to treat human sepsis patients. The role of PPARα in liver dysfunction during sepsis has recently been described, and restoring PPARα signaling proves to be successful in murine sepsis. To find out whether this therapy might also be helpful in human sepsis patients, we analyzed metabolic perturbations in liver of a porcine fecal peritonitis model. Resuscitation with fluids, antimicrobial therapy and abdominal drainage were applied to the pigs in order to mimic human clinical care. By using RNA-seq, we detected problems with PPARα signaling in the livers of septic pigs and reduced PPARα levels correlated well with disease severity. As PPARα regulates the expression of many genes involved in FA oxidation, reduced expression of these target genes concomitant with increased FFAs in plasma and ectopic lipid deposition in the liver was observed. The results obtained in pigs are in agreement with earlier observations in mice and support the potential of targeting defective PPARα signaling in the clinic.
2022-11-28 | GSE218636 | GEO
Project description:BACKGROUND: Toll-like receptors (TLRs) are critical components for host pathogen recognition and variants in genes participating in this response influence susceptibility to infections. Recently, TLR1 gene polymorphisms have been found correlated with whole blood hyper-inflammatory responses to pathogen-associated molecules and associated with sepsis-associated multiorgan dysfunction and acute lung injury (ALI). We examined the association of common variants of TLR1 gene with sepsis-derived complications in an independent study and with serum levels for four inflammatory biomarkers among septic patients. METHODOLOGY/PRINCIPAL FINDINGS: Seven tagging single nucleotide polymorphisms of the TLR1 gene were genotyped in samples from a prospective multicenter case-only study of patients with severe sepsis admitted into a network of intensive care units followed for disease severity. Interleukin (IL)-1?, IL-6, IL-10, and C-reactive protein (CRP) serum levels were measured at study entry, at 48 h and at 7(th) day. Alleles -7202G and 248Ser, and the 248Ser-602Ile haplotype were associated with circulatory dysfunction among severe septic patients (0.001 ? p ? 0.022), and with reduced IL-10 (0.012 ? p ? 0.047) and elevated CRP (0.011 ? p ? 0.036) serum levels during the first week of sepsis development. Additionally, the -7202GG genotype was found to be associated with hospital mortality (p = 0.017) and ALI (p = 0.050) in a combined analysis with European Americans, suggesting common risk effects among studies. CONCLUSIONS/SIGNIFICANCE: These results partially replicate and extend previous findings, supporting that variants of TLR1 gene are determinants of severe complications during sepsis.
| S-EPMC2966434 | biostudies-literature
Project description:An early aspect of sepsis is dysregulated activation of endothelial cells (EC), initiating a cascade of inflammatory signaling leading to leukocyte adhesion/migration and organ damage. Therapeutic targeting of ECs has been hampered by concerns regarding ECs heterogeneity from different organs. Using a combination of in vitro and in silico analysis, we present a comprehensive analysis of proteomic changes in mouse lung, kidney and liver ECs following exposure to a clinically relevant cocktail of proinflammatory cytokines. Mouse lung, liver and kidney ECs were incubated with TNFα/IL-1β/IFNγ for 4 or 24 hrs to model inflammatory responses during sepsis. Quantitative label-free global proteomics was performed on the ECs to identify differentially expressed proteins (DEP). Proteins with an abundance ratio >2.0 or <0.5 and an adjusted p<0.05 were characterized as upregulated or downregulated respectively. Gene Ontology (GO) classification was used to determine biological processes that regulate EC function during sepsis and PANTHER was used to classify the molecular function of the identified proteins. Finally, an interactive pathway was developed to investigate signaling within ECs and across organs. Proteomic analysis identified both unique and shared DEPs between the ECs specific to lung, liver and kidney. Using GO, 5 Biological Processes (BP) for each of the organ specific ECs were identified. Interestingly, 4 of the top 5 GO BPs were observed in all 3 ECs at 4 and 24 hrs: defense response to other organism, innate immune response, response to bacterium and response to cytokine. However, these BPs were found to be differentially regulated. For example, at 4 and 24 hrs, lung ECs which have the highest number and highest fold expression of upregulated proteins (189 and 316 respectively), also have higher numbers of unique upregulated proteins (124 vs 194) compared to liver (98 vs 121) and kidney ECs (109 vs 136). The liver showed the greatest number of conserved proteins between 4 and 24 hrs (56) compared to lung (50) and kidney (51). The number of common proteins between all three ECs increases from 38 at 4 hrs to 79 at 24 hrs, indicating more uniformity in ECs proteomic expression during the progression of sepsis. The PANTHER database was used to classify proteins in different functional groups (e.g. defense/immunity) at 4 and 24 hrs. Thus, BPs and PANTHER hits can provide insight into why some organs are more susceptible to sepsis early on and show that as sepsis progresses, some protein expression patterns become more uniform while additional organ specific proteins are expressed. Proteomic analysis of organ-specific ECs provides further understanding of how sepsis affects multiple organs across time and supports future proteomic, temporal studies of EC dysfunction.
2022-10-14 | PXD031804 | Pride
Project description:Blood monocytes serve as the first line of host defense and are equipped to recognize and respond to infection by triggering an immune-inflammatory response. While most information on these cells comes from in vitro studies in humans or in vivo studies in mice, little is known about monocytes under human disease conditions. We investigated the role of monocytes during sepsis and its resolution in humans. A transcriptomal and functional analysis of blood monocytes from patients during gram negative sepsis and at recovery was performed. Monocytes from sepsis patients showed upregulation of a large number of pro-inflammatory genes and cytokines/chemokines, consistent with an ongoing systemic inflammation. However, these cells showed impairment to ex vivo endotoxin (LPS) challenge, displaying a quantitative decrease in the number of LPS-inducible genes. Moreover, they downregulated the expression of several pro-inflammatory cytokine/chemokine genes, activation marker genes and transcription factors associated with monocyte/macrophage activation, upon ex vivo LPS stimulation. Functionally, they downregulated expression of inflammatory cytokines/chemokines and antigen presentation-related molecules and functions. In contrast, genes and functions related to phagocytosis, anti-microbial activity and tissue remodeling where remained unaffected or even enhanced . Collectively, our observations suggest a genetic and functional re-programming of these cells during human sepsis progression. Understanding the molecular mechanisms which regulate this re-programming will allow to devise strategies which could modulate the response of these cells and hence, disease progression. Blood monocytes from gram-negative sepsis patients during sepsis (Sepsis) and following their recovery (Recovery/Basal) as well as healthy donor (control) were isolated. Thereafter, these cells were treated ex vivo with or without LPS for 3h and analysed for transcriptomic study.
2014-05-14 | E-GEOD-46955 | biostudies-arrayexpress