Interferon-gamma 1b-Induced Gene Expression Alters Neutrophil Function in Patients with Chronic Granulomatous Disease
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ABSTRACT:
PROVIDER: PRJEB71509 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR12387900_1.fastq.gz | Fastqsanger.gz | |||
| ERR12387900_2.fastq.gz | Fastqsanger.gz | |||
| ERR12387901_1.fastq.gz | Fastqsanger.gz | |||
| ERR12387901_2.fastq.gz | Fastqsanger.gz | |||
| ERR12387902_1.fastq.gz | Fastqsanger.gz |
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Project description:IFNG decreases incidence of infections in chronic granulomatous disease (CGD) without affecting inability of CGD neutrophils to generate essential microbicidal oxidants. Neutrophil (PMN) function, gene expression, and biochemical parameters were measured off IFN-γ and 10-12 hours after 1st and 4th doses of IFN-γ administered to nine CGD patients. Non-directed motility and bactericidal activity were increased after treatment with IFN-γ; ingestion and O2- generation remained unchanged. Treatment decreased expression of 483 genes and increased 386. Genes (11) associated with PMN activity were upregulated. Genes not routinely associated with neutrophil function were increased including MHCI and II, guanylate binding proteins, and an enzyme synthesizing a NOS cofactor. CD11b expression, f-Actin assembly, and CD 274 antigen were increased after treatment as was NO in PMN lysates. NETs formation after ingestion was increased off IFN- but moved toward normal after administration. IFN- provides neutrophils with strategies to compensate for the deficiency found in CGD.
2024-07-01 | E-MTAB-13674 | biostudies-arrayexpress
Project description:The cytokine interferon-gamma (IFN-gamma) is used as a drug to treat Chronic Granulomatous Disease (CGD), a group of genetic disorders characterized by defects in components of the neutrophil-resident NADPH oxidase/Nox2 enzyme system. Administration of IFN-gamma to these patients results in decreased incidents of severe infection, but has no effect on the characteristic defect of CGD, the inability to convert oxygen to microbicidal reactive oxygen species. To determine the mechanism by which IFN-gamma enhances the host protective properties of neutrophils, we administered INF-gamma to 10 healthy adult volunteers and carried out transcription profiling by array for neutrophils isolated from their peripheral blood. IFN-gamma was administered to each subject at 4 doses (10, 25, 50 and 100 micrograms/meter squared) with washout periods between each dose. Gene expression levels in neutrophils were measure just before (time 0) and at various times (4, 8, 12, 24, 36, 48, 72 and 96 hours) after administration of IFN-gamma. In the list of samples, individual patients are indicated by 01-10, the dose by D10, D25, D50 and D100, referring to 10, 25, 50 and 100 micrograms / meter squared respectively and the times by visit (V) numbers where VI, V2, V3, V4, V5, V6, V7, V8 and V9 refer to the 0 4, 8, 12, 24, 36, 48, 72 and 96 hour time points respectively.
2018-12-14 | E-MTAB-7261 | biostudies-arrayexpress
Project description:Interleukin 1b and interferon g are two cytokines that are central to the inflammatory response. They both have a broad range of activity, each directing the immune response to be towards either the innate response (IL-1b and IFN-g) or the cellular response (IFN-g), however invivo there is a lot of subtle interactions. Microarray analysis has been used to characterize the transcriptional response to recombinant rainbow trout IL-1b and IFN-g in a rainbow trout macrophage cell line RTS-11. The use of the cell line removes the host response and the interference of other cellular factors that occur when performing whole fish experiments, or even primary cultures. RNA was extracted from stimulated or control cells following 6h incubation, this was used to hybridize to a 16K v1 salmonid cDNA array constructed by GRASP consortium. Keywords: Dual label cDNA microarray
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Project description:Interferon-gamma (IFN-gamma) is approved as a drug to treat chronic granulomatous disease and osteopetrosis and is also used in hyperimmunoglobulin E syndromes. These primary immunodeficiencies involve defects in neutrophils/polymorphonuclear cells. Neutrophils mature in the bone marrow and then enter the blood where they quickly undergo apoptotic cell death with a half-life of 5-10 hours. Therefore we reasoned that IFN-gamma might exert its effects on neutrophils via prolonged exposure to cells undergoing maturation toward a terminally differentiated state in the marrow rather than by its brief exposure to short-lived circulating cells. To explore this possibility we made use of PLB-985 cells which are a myeloblast-like myeloid cell line that can be differentiated into a mature, neutrophil-like state by treatment with various agents including DMSO. In initial studies we investigated transcription and protein expression in PLB-985 cells undergoing DMSO-mediated maturation in the presence or absence of IFN-gamma and identified several classes of immunity related genes that were differentially expressed in the presence of the drug and could potentially explain the immune supportive properties of IFN-gamma. Next we explored if the effect of IFN-gamma on expression of these genes is dependent on whether the cells are undergoing maturation; to do this we compared the effects of IFN-gamma on cells cultured with and without DMSO. For a subset of genes the expression level changes caused by IFN-gamma were much greater in maturing cells than non-maturing cells. These findings indicate that developmental changes associated with cell maturation can modulate the effects of IFN-gamma and supports our hypothesis that the effects of the drug on developing neutrophils in the bone marrow may be very different from its effects on mature cells in the blood. We also compared the effects on gene expression of applying IFN-gamma either during DMSO mediated PLB-985 cell maturation or after maturation i.e. IFN-gamma was applied to already mature cells. For some genes we found that IFN-gamma applied to mature cells caused large changes in expression similar to those seen when IFN-gamma was applied during maturation, however for other genes no effect was seen when drug was applied to mature cells but large effects were seen when drug was applied during DMSO treatment. This data suggests that, in the former class of genes, the effects of IFN-gamma application during maturation are largely the result of the effects of the drug on cells approaching full maturity but in the latter class of genes the effects of IFN-gamma only become apparent when it is present throughout maturation. This further supports our hypothesis that the effects of IFN-gamma are modulated by developmental changes associated with cell maturation.
2017-08-31 | E-MTAB-5690 | biostudies-arrayexpress
Project description:Interferon-γ (IFN-γ) plays an important role in innate and adaptive immunity against intracellular infections and is used clinically for the prevention and control of infections in chronic granulomatous disease (CGD) and inborn defects in the IFN-γ/interleukin (IL)-12 axis. Using transcriptome profiling (RNA-seq), we sought to identify differentially expressed genes, transcripts and exons in Epstein-Barr virus-transformed B lymphocytes (B-EBV) cells from CGD patients, IFN-γ receptor deficiency patients, and normal controls, treated in vitro with IFN-γ for 48 hours. Our results show that IFN-γ increased the expression of a diverse array of genes related to different cellular programs. In cells from normal controls and CGD patients, IFN-γ-induced expression of genes relevant to oxidative killing, nitric oxide synthase pathway, proteasome-mediated degradation, antigen presentation, chemoattraction, and cell adhesion. IFN-γ also upregulated genes involved in diverse stages of messenger RNA (mRNA) processing including pre-mRNA splicing, as well as others implicated in the folding, transport, and assembly of proteins. In particular, differential exon expression of WARS (encoding tryptophanyl-transfer RNA synthetase, which has an essential function in protein synthesis) induced by IFN-γ in normal and CGD cells suggests that this gene may have an important contribution to the benefits of IFN-γ treatment for CGD. Upregulation of mRNA and protein processing related genes in CGD and IFNRD cells could mediate some of the effects of IFN-γ treatment. These data support the concept that IFN-γ treatment may contribute to increased immune responses against pathogens through regulation of genes important for mRNA and protein processing.
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Project description:Systemic lupus erythematosus (SLE) is characterized by upregulation of Type Ι Interferon (IFN) and widespread inflammation. However, blocking the IFN pathway benefits a fraction of patients, pointing to additional pathogenic players. Here we describe monocytes (Mo) undergoing erythrophagocytosis and co-expressing IFN-inducible genes (ISGs) and interleukin-1b (IL-1b) in patients with active disease. This phenotype is recapitulated in vitro upon internalization of red blood cells carrying mitochondria (Mito+ RBCs), a feature of SLE. While ISG expression requires the interaction between Mito+ RBC-derived mitochondrial DNA (mtDNA) and cGAS, the production of IL-1b entails Mito+ RBC-derived mitochondrial RNA (mtRNA) triggering RIG-I-like receptor (RLR) activation. This leads to the cytosolic release of Mo-derived mtDNA and activation of the NLRP3 inflammasome. Importantly, the Type I IFN-inducible protein myxovirus resistant protein 1 (MxA) enables IL-1b release by routing this cytokine into a trans-Golgi network (TGN)-mediated unconventional secretory pathway. As Type I IFN and IL-1b are thought to counter-regulate each other, our study highlights an unprecedented synergy between these two cytokine pathways in SLE.
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Project description:A growing body of evidence suggests that inflammatory cytokines have a dualistic role in immunity. In this study, we sought to determine the direct effects IFN-gamma on the differentiation and maturation of human peripheral blood monocyte-derived dendritic cells (moDC). Here, we report that following differentiation of human peripheral-blood monocytes into moDCs with granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-4, interferon-gamma (IFN-gamma) induces moDC maturation and up-regulates the co-stimulatory markers CD80, CD86, CD95, and MHC Class I, enabling moDCs to effectively generate antigen-specific CD4+ and CD8+ T cell responses for multiple viral and tumor antigens. Interestingly, early exposure of monocytes to high concentrations of IFN-gamma promotes monocyte differentiation into macrophages, despite the presence of GM-CSF and IL-4. However, under low concentrations of IFN-gamma, monocytes continue to differentiate into dendritic cells possessing a unique gene-expression profile, resulting in impairments in subsequent maturation by IFN-gamma and an inability to generate effective antigen-specific CD4+ and CD8+ T cell responses compared to standard moDCs. Monocytes differentiated in the presence of low levels of IFN-gamma downregulate IFN-gamma receptor expression, impairing their response to an inflammatory rechallenge. These findings demonstrate the ability of IFN-gamma to impart differential programs on human moDCs which shape the antigen-specific T cell responses they induce. Timing and intensity of exposure to IFN-gamma can thus determine whether moDCs are tolerogenic or immunostimulating. Human monocyte-derived dendritic cells from 4 healthy donors were differentiated with either GM-CSF and IL-4 (n=4) or GM-CSF, IL-4, and IFN-gamma (n=4). These samples were subsequently hybridized to arrays as 4 biological repeats for each of the two treatment conditions.
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Project description:BACKGROUND: We have shown previously that acute infection with the respiratory pathogen, pneumonia virus of mice (PVM), results in local production of the proinflammatory chemokine, CCL3, and that neutrophil recruitment in response to PVM infection is reduced dramatically in CCL3 -/- mice. RESULTS: In this work, we demonstrate that CCL3-mediated neutrophil recruitment is coordinated by interferon-gamma (IFNgamma). Neutrophil recruitment in response to PVM infection was diminished five-fold in IFNgamma receptor gene-deleted mice, although neutrophils from IFNgammaR -/- mice expressed transcripts for the CCL3 receptor, CCR1 and responded functionally to CCL3 ex vivo. Similarly, in the absence of PVM infection, CCL3 overexpression alone could not elicit neutrophil recruitment in the absence of IFNgamma. Interestingly, although supplemental IFNgamma restored neutrophil recruitment and resulted in a sustained weight loss among CCL3-overexpressing IFNgamma -/- mice, CCL3-mediated neutrophil recruitment alone did not result in the pulmonary edema or respiratory failure characteristic of severe viral infection, suggesting that CCL3 and IFN-gamma together are sufficient to promote neutrophil recruitment but not pathologic activation. CONCLUSION: Our findings reveal a heretofore unrecognized hierarchical interaction between the IFNgamma and CCL3, which demonstrate that IFNgamma is crucial for CCL3-mediated neutrophil recruitment in vivo.
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Project description:Systemic immune responses induced by chronic hypercholesterolemia contribute to the initiation, progression and complications of atherosclerosis. However, the consequences of an alternate high fat diet and the associated variations in plasma cholesterol levels on atherosclerosis are unknown. To address this relevant issue concerning common situations where dietary habits change over time, we developed a novel protocol in athero-prone mice that allowed us to compare the effects of alternate versus continuous high fat diet (HFD) on atherosclerosis, the overall period of time of exposure to HFD being similar between groups. We showed that alternate HFD lead to accelerated atherosclerosis in Ldlr-/- and Apoe-/- mice compared to continuous HFD. The pro-atherogenic effect of alternate HFD was also found in Apoe-/-Rag2-/- mice lacking T, B, and NKT cells, ruling out a role for the adaptive immune system in the observed phenotype. Using different complementary in vivo approaches, we found that lipid-rich diet discontinuation in alternate group downregulated Runx1, a negative regulator downstream of TLR-4 pathways. As a result, after re-exposure to HFD, myeloid progenitors were more sensitive to hypercholesterolemia leading to acute differentiation into IL-1b- producing immature neutrophils, which caused a state of emergency myelopoiesis. Consecutively, neutrophils markedly increased in the peripheral blood, infiltrated atherosclerotic lesions and locally released neutrophil extracellular traps. Anti-Ly6G neutrophil depletion abolished the pro-atherogenic effects of alternate HFD. Specific deletion of Il1b and Il1b receptor confirmed that the IL-1b signaling pathway was a major driver of the pro-inflammatory and pro-atherogenic neutrophil signature. Finally, treatment with anti-IL-1b neutralizing antibody or inflammasome inhibitor during re-exposure to HFD reversed the pro-atherogenic effects of alternate HFD. In summary, we showed that alternate HFD accelerates atherosclerosis through IL-1b-dependent neutrophil progenitor reprogramming.
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