Associations of inflammation, iron and early death in sickle cell disease
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE53441 | GEO | 2014/12/31
SECONDARY ACCESSION(S): PRJNA231999
REPOSITORIES: GEO
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Project description:Rationale. Sickle cell cardiomyopathy is characterized by prolonged QTc, myocardial fibrosis, diastolic dysfunction, and vulnerability to ventricular tachycardia (VT). Based on previous reports, IL-18 mediates cardiac fibrosis and its promoter SNPs are associated with sudden cardiac death in a non-sickle population. We, therefore, hypothesized that IL-18 may mediate cardiomyopathy and VT in sickle cell disease. Findings. Sickle cell patients with evidence of myocardial fibrosis demonstrated greater IL18 expression. Patients with higher IL18 gene expression levels also exhibited increased QTc intervals and overall mortality. A novel SNP within IL-18, rs5744285, was associated with both QTc and IL-18 expression levels. Similar to sickle cell patients, sickle mice demonstrated increased cardiac fibrosis and prolonged action potential duration (APD) associated with higher VT inducibility. Administration of exogenous IL-18 acutely ex vivo to hearts resulted in increased triggered activity and VTs while inhibition of IL-18 resulted in reduced cardiac NFkB expression, fibrosis, and dysfunction in sickle mice. Conclusions. IL-18 is associated with prolonged QTc, myocardial fibrosis, and mortality in sickle cell patients, and prolonged APD associated with heightened VT susceptibility in sickle mice. Inhibition of IL-18 improves cardiac function, in part, via NFκB. Inflammatory cytokines contribute to the development of sickle cardiomyopathy and inducible VT.
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Project description:Transcriptional changes in compensatory erythropoiesis in sickle cell anemia (SCA) and their disease modulation are unclear. We detected 1226 differentially expressed genes in hemoglobin SS reticulocytes compared to non-anemic hemoglobin AA controls. Assessing developmental expression changes in hemoglobin AA erythroblasts for these genes suggests heightened terminal differentiation in early erythroblasts in SCA that diminishes toward the polychromatic to orthochromatic stage transition. Comparison of reticulocyte gene expression changes in SCA with that in Chuvash erythrocytosis, a non-anemic disorder of increased erythropoiesis due to constitutive activation of hypoxia inducible factors, identified 453 SCA-specific changes attributable to compensatory erythropoiesis. Peripheral blood mononuclear cells (PBMCs) in SCA contain elevated proportions of erythroid progenitors due to heightened erythropoiesis. Deconvolution analysis in PBMCs from 131 SCA patients detected 54 genes whose erythroid expression correlated with erythropoiesis efficiency, which were enriched with SCA-specific changes (OR=2.9, P=0.00063) and annotation keywords of “ubiquitin-dependent protein catabolic process” and “protein ubiquitination” (OR=4.1, P=9.6×10-5). An erythroid expression quantitative trait locus of one of these genes, LNX2 encoding an E3 ubiquitin ligase, associated with severe pain episodes in 774 SCA patients (OR=1.7, P=3.9×10-5). Thus, erythroid gene transcription responds to unique conditions within SCA erythroblasts and these changes potentially correspond to vaso-occlusive manifestations.
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Project description:Polymorphonuclear neutrophils are key actors in the pathophysiology of sickle cell disease, but specific factors underlying their activation and sustained inflammation are not well documented. In the present study, we investigated the proteome of neutrophils by a label-free global comparative approach between 4 non-treated sickle patients (SS genotype) at steady state and 4 healthy donors. We identified 101 proteins differentially expressed in SS and normal neutrophils. We found overexpression of CD64 and under-expression of CD62L suggestive of an activated and aged neutrophil profile in SS patients. Comparison of the two proteomes revealed a strong involvement of the type 1 interferon (IFN) response pathway with a 3- to 84-fold increase of type 1 IFN-induced proteins in SS neutrophils, and overexpression of STAT1 and STAT2. Thus, we next determined the plasmatic concentration of type 1 IFNs (IFNα and IFNβ) using the digital-ELISA technology and found a significant higher concentration of IFNα in the plasma from half of our SS patients compared to controls. Overall, a dramatic high-level expression of IFNα signaling proteins in neutrophils from SS patients suggests auto-inflammatory-like phenotype in sickle cell disease at steady state. This finding could open the way to new anti-inflammatory therapies.
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Project description:In sickle cell disease, ischemia-reperfusion injury and intravascular hemolysis produce endothelial dysfunction and vasculopathy characterized by reduced nitric oxide (NO) and arginine bioavailability. Recent functional studies of platelets in patients with sickle cell disease reveal a basally activated state, suggesting that pathological platelet activation may contribute to sickle cell disease vasculopathy. Studies were therefore undertaken to examine transcriptional signaling pathways in platelets that may be dysregulated in sickle cell disease. We demonstrate and validate here the feasibility of comparative platelet transcriptome studies on clinical samples from single donors, by the application of RNA amplification followed by microarray-based analysis of 54,000 probe sets. Data mining an existing microarray database, we identified 220 highly abundant genes in platelets and a subset of 72 relatively platelet-specific genes, defined by more than 10-fold increased expression compared to the median of other cell types in the database with amplified transcripts. The highly abundant platelet transcripts found in the current study included 82% or 70% of platelet abundant genes identified in two previous gene expression studies on non-amplified mRNA from pooled or apheresis samples, respectively. On comparing the platelet gene expression profiles in 18 patients with sickle cell disease in steady state to 12 African American controls, at a 3-fold cut-off and 5% false discovery rate, we identified ~100 differentially expressed genes, including multiple genes involved in arginine metabolism and redox homeostasis. Further characterization of these pathways using real time PCR and biochemical assays revealed increased arginase II expression and activity and decreased platelet polyamine levels. These studies suggest a potential pathogenic role for platelet arginase and altered arginine and polyamine metabolism in sickle cell disease and provide a novel framework for the study of disease-specific platelet biology. Experiment Overall Design: There are 18 sickle cell samples and 12 control samples from healthy African American volunteers.
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