E-GEOD-38351
Ontology highlight
ABSTRACT:
OTHER RELATED OMICS DATASETS IN: PRJNA168483
PROVIDER: E-GEOD-38351 | ExpressionAtlas | 2019-05-21
REPOSITORIES: ExpressionAtlas
Similar Datasets
Project description:The multifaceted balance of TNF-a and type I / II interferon responses in SLE and RA: how monocytes manage the impact of cytokines
| PRJNA168483 | ENA
Project description:The effect of human immunodeficiency virus (HIV) infection and high-level HIV replication on the function of monocytes was investigated. HIV-positive patients had elevated levels of spontaneous production of some or all of the monocyte proinflammatory cytokines measured (interleukin-1beta [IL-1beta], IL-6, and tumor necrosis factor alpha [TNF-alpha]) compared to uninfected controls. In patients on therapy with high frequencies of monocytes producing proinflammatory cytokines, this frequency was diminished in the context of viremia during an interruption of therapy. Diminished production of proinflammatory cytokines during viremia was restored by culture with autologous CD4(+) T cells or monocytes from an on-therapy time point or lipopolysaccharide (LPS). Microarray analysis demonstrated that diminished monocyte production of proinflammatory cytokines was correlated with elevated type I interferon-stimulated gene transcripts. The addition of exogenous alpha 2A interferon diminished the spontaneous production of IL-1beta, IL-6, and TNF-alpha but did not affect responses to LPS, recapitulating the changes observed for HIV-viremic patients. These results suggest that monocyte function is diminished during high-level HIV viremia and that this effect is mediated by chronic stimulation by type I interferons. This effect on monocytes during viremia may play a role in diminished innate or adaptive immune system functions in HIV-infected patients. In addition, the restoration of these functions may also play a role in some immune reconstitution syndromes observed during initiation of therapy.
2007-10-26 | E-GEOD-5220 | biostudies-arrayexpress
Project description:Longitudinal analysis of monocyte gene expressions patterns before and after cessation of HAART: understanding the impact of HIV viremia on the monocyte tranascritome. We used microarrays to detail the global program of gene expression underlying defects in monocytes from HIV infected patients during viremia.. Diminished Production of Monocyte Proinflammatory Cytokines During HIV Viremia is Mediated by Interferon-alpha: The in vivo effect of high-level HIV replication on the function of monocytes was investigated. HIV-positive patients had elevated spontaneous production of monocyte proinflammatory cytokines (IL-1?, IL-6, and TNF-?) compared to uninfected controls. These levels were highest in patients on-therapy and was diminished, in the context of viremia, following an interruption of therapy. Diminished production of proinflammatory cytokines during viremia was restored by culturing with autologous CD4+ T cells or monocytes from an on-therapy time point, or by the addition of lipopolysaccharide (LPS). Microarray analysis demonstrated that diminished monocyte production of proinflammatory cytokines was correlated with elevated levels of type I interferon-stimulated gene transcripts. Addition of exogenous IFN-?2A suppressed the spontaneous production of IL-1?, IL-6, and TNF-? but did not affect responses to LPS, recapitulating the changes observed in HIV viremic patients. These results suggest that high-level HIV viremia inhibits monocyte function through chronic stimulation by IFN-?. This effect of viremia on monocytes may play a role in diminished adaptive immune system functions in HIV-infected patients. Restoration of these functions may contribute to the partial immune reconstitution observed following therapy and may be involved in immune reconstitution and inflammatory syndrome seen in some patients. Keywords: Longitudinal comparison
2006-07-04 | GSE5220 | GEO
Project description:NYVAC, a highly attenuated, replication-restricted poxvirus, is a safe and immunogenic vaccine vector. Deletion of immune evasion genes from the poxvirus genome is an attractive strategy for improving the immunogenic properties of poxviruses. Using systems biology approaches, we describe herein the enhanced immunological profile of NYVAC vectors expressing the HIV-1 clade C env, gag, pol, and nef genes (NYVAC-C) with single or double deletions of genes encoding type I (B19R) or type II (B8R) interferon (IFN)-binding proteins. Transcriptomic analyses of human monocytes infected with NYVAC-C, NYVAC-C with the B19R deletion (NYVAC-C- B19R), or NYVAC-C with B8R and B19R deletions (NYVAC-C- B8RB19R) revealed a concerted upregulation of innate immune pathways (IFN-stimulated genes [ISGs]) of increasing magnitude with NYVAC-C- B19R and NYVAC-C- B8RB19R than with NYVAC-C. Deletion of B8R and B19R resulted in an enhanced activation of IRF3, IRF7, and STAT1 and the robust production of type I IFNs and of ISGs, whose expression was inhibited by anti-type I IFN antibodies. Interestingly, NYVAC-C- B8RB19R induced the production of much higher levels of proinflammatory cytokines (tumor necrosis factor [TNF-], interleukin-6 [IL-6], and IL-8) than NYVAC-C or NYVAC-C- B19R as well as a strong inflammasome response (caspase-1 and IL-1 ) in infected monocytes. Top network analyses showed that this broad response mediated by the deletion of B8R and B19R was organized around two upregulated gene expression nodes (TNF and IRF7). Consistent with these findings, monocytes infected with NYVAC-C- B8RB19R induced a stronger type I IFN-dependent and IL-1-dependent allogeneic CD4 T cell response than monocytes infected with NYVAC-C or NYVAC-C- B19R. Dual deletion of type I and type II IFN immune evasion genes in NYVAC markedly enhanced its immunogenic properties via its induction of the increased expression of type I IFNs and IL-1 and make it an attractive candidate HIV vaccine vector. Primary Human monocytes from 5 donors were incubated with each following vectors nyvacdb, nyvadb19r, nyvaccdb8rb19r_6h, untreated control and collected at 6h.
2015-01-30 | E-GEOD-65412 | biostudies-arrayexpress
Project description:NYVAC, a highly attenuated, replication-restricted poxvirus, is a safe and immunogenic vaccine vector. Deletion of immune evasion genes from the poxvirus genome is an attractive strategy for improving the immunogenic properties of poxviruses. Using systems biology approaches, we describe herein the enhanced immunological profile of NYVAC vectors expressing the HIV-1 clade C env, gag, pol, and nef genes (NYVAC-C) with single or double deletions of genes encoding type I (B19R) or type II (B8R) interferon (IFN)-binding proteins. Transcriptomic analyses of human monocytes infected with NYVAC-C, NYVAC-C with the B19R deletion (NYVAC-C- B19R), or NYVAC-C with B8R and B19R deletions (NYVAC-C- B8RB19R) revealed a concerted upregulation of innate immune pathways (IFN-stimulated genes [ISGs]) of increasing magnitude with NYVAC-C- B19R and NYVAC-C- B8RB19R than with NYVAC-C. Deletion of B8R and B19R resulted in an enhanced activation of IRF3, IRF7, and STAT1 and the robust production of type I IFNs and of ISGs, whose expression was inhibited by anti-type I IFN antibodies. Interestingly, NYVAC-C- B8RB19R induced the production of much higher levels of proinflammatory cytokines (tumor necrosis factor [TNF-], interleukin-6 [IL-6], and IL-8) than NYVAC-C or NYVAC-C- B19R as well as a strong inflammasome response (caspase-1 and IL-1 ) in infected monocytes. Top network analyses showed that this broad response mediated by the deletion of B8R and B19R was organized around two upregulated gene expression nodes (TNF and IRF7). Consistent with these findings, monocytes infected with NYVAC-C- B8RB19R induced a stronger type I IFN-dependent and IL-1-dependent allogeneic CD4 T cell response than monocytes infected with NYVAC-C or NYVAC-C- B19R. Dual deletion of type I and type II IFN immune evasion genes in NYVAC markedly enhanced its immunogenic properties via its induction of the increased expression of type I IFNs and IL-1 and make it an attractive candidate HIV vaccine vector.
2015-01-30 | GSE65412 | GEO
Project description:Monocytes are the key mediators of inflammatory responses in virus patients, and are also the only blood cell type that supports productive infection both in vitro and in vivo. In this study, we assessed how dengue infection alters the metabolic response of monocytes and affects ensuing inflammatory mechanisms. Using a glycostress assay, we showed that in vitro infected primary human monocytes by dengue virus and monocytes isolated from thrombocytopenic dengue patients, during critical stage of the disease, had increased glycolysis. Single cell transcriptomics revealed an enhanced expression of interferon-related genes and glycolytic genes in classical and intermediate monocytes of dengue patients with more pronounced thrombocytopenia. Targeting glycolysis by 2-deoxy-glucose (2DG) reduced dengue infection and dampened pro-inflammatory cytokines in monocytes, both in vitro and in mouse models. Collectively, these results suggest that glycolysis could be a possible target for pharmaceutical intervention to regulate pathogenic host responses in dengue.
2021-04-02 | GSE171290 | GEO
Project description:IRAK4 kinase plays a critical role in innate immune responses and inflammation by modulating the TLR/IL-1R signaling pathway, yet the mechanism by which it regulates downstream pathways and transcription factors to induce inflammatory cytokines is unclear. IRAK4 can mediate signaling events by mechanisms both dependent and independent of its kinase activity. Understanding this regulation is important for deciphering the role of IRAK4 and for the development of treatments for inflammatory diseases and cancer. Through transcriptomic and biochemical analyses of primary human monocytes treated with a highly potent and selective inhibitor of IRAK4, we show that IRAK4 kinase activity controls the transcription factor IRF5 which in turn induces inflammatory cytokine and type I interferon transcription in myeloid cells. We also show that IRAK4 kinase activity does not control activation of NF-κB. Following TLR stimulation, translocation of IRF5, but not NF-κB, to the nucleus in human monocytes is abolished by IRAK4 kinase inhibition. In addition, binding of IRF5, but not NF-κB p65, to promoters of inflammatory target genes (TNF-α and IP10) is blocked with an IRAK4 kinase inhibitor. IKKβ, a known activator of IRF5, is phosphorylated in response to TLR mediated signaling, and inhibition of IRAK4 kinase blocks IKKβ phosphorylation. Pharmacological inhibition of IKKβ and TAK1, the upstream kinase of IKKβ, in human monocytes blocks IL-1, IL-6 and TNF-α cytokine production, as well as IRF5 translocation to the nucleus. Taken together, our data suggest a novel mechanism by which IRAK4 kinase activity regulates TAK1 and IKKβ activation, leading to the translocation of IRF5 and induction of inflammatory cytokines in human monocytes.
2017-10-12 | GSE86234 | GEO
Project description:Macrophages are critical components of atherosclerotic lesions and their pro- and anti-inflammatory responses influence atherogenesis. Type-I interferons (IFNs) are cytokines that play an essential role in antiviral responses and inflammatory activation and have been shown to promote atherosclerosis. Although the impact of type-I IFNs on macrophage foam cell formation is well-documented, the effect of lipid accumulation in monocytes and macrophages on type-I IFN responses remains unknown. Here we examined IFN stimulated (ISG) and non-ISG inflammatory gene expression in mouse and human macrophages that were loaded with acetylated LDL (acLDL), as a model for foam cell formation. We found that acLDL loading in mouse and human macrophages specifically suppressed expression of ISGs and IFN-β secretion, but not other pro-inflammatory genes. The down regulation of ISGs could be rescued by exogenous IFN-β supplementation. Activation of the cholesterol-sensing nuclear liver X receptor (LXR) recapitulated the cholesterol-initiated type-I IFN suppression. Additional analyses of murine in vitro and in vivo generated foam cells confirmed the suppressed IFN signaling pathways and suggest that this phenotype is mediated via down regulation of interferon regulatory factor binding at gene promoters. Finally, RNA-seq analysis of monocytes of familial hypercholesterolemia (FH) patients also showed type-I IFN suppression which was restored by lipid-lowering therapy and not present in monocytes of healthy donors. Taken together, we define type-I IFN suppression as an athero-protective characteristic of foamy macrophages. These data provide new insights into the mechanisms that control inflammatory responses in hyperlipidaemic settings and can support future therapeutic approaches focusing on reprogramming of macrophages to reduce atherosclerotic plaque progression and improve stability.
2022-07-01 | GSE193118 | GEO
Project description:Macrophages are critical components of atherosclerotic lesions and their pro- and anti-inflammatory responses influence atherogenesis. Type-I interferons (IFNs) are cytokines that play an essential role in antiviral responses and inflammatory activation and have been shown to promote atherosclerosis. Although the impact of type-I IFNs on macrophage foam cell formation is well-documented, the effect of lipid accumulation in monocytes and macrophages on type-I IFN responses remains unknown. Here we examined IFN stimulated (ISG) and non-ISG inflammatory gene expression in mouse and human macrophages that were loaded with acetylated LDL (acLDL), as a model for foam cell formation. We found that acLDL loading in mouse and human macrophages specifically suppressed expression of ISGs and IFN-β secretion, but not other pro-inflammatory genes. The downregulation of ISGs could be rescued by exogenous IFN-β supplementation. Activation of the cholesterol-sensing nuclear liver X receptor (LXR) recapitulated the cholesterol-initiated type-I IFN suppression. Additional analyses of murine in vitro and in vivo generated foam cells confirmed the suppressed IFN signalling pathways and suggest that this phenotype is mediated via downregulation of interferon regulatory factor binding at gene promoters. Finally, RNA-seq analysis of monocytes of familial hypercholesterolemia (FH) patients also showed type-I IFN suppression which was restored by lipid-lowering therapy and not present in monocytes of healthy donors. Taken together, we define type-I IFN suppression as an athero-protective characteristic of foamy macrophages. These data provide new insights into the mechanisms that control inflammatory responses in hyperlipidaemic settings and can support future therapeutic approaches focusing on reprogramming of macrophages to reduce atherosclerotic plaque progression and improve stability.
2022-02-10 | GSE192709 | GEO
Project description:Begitt2014 - STAT1 cooperative DNA binding - single GAS polymer model
The importance of STAT1-cooperative DNA binding in type 1 and type 2 interferon signalling has been studies using experimental and modelling approaches. The authors have developed two ODE models to describe STAT1 binding to short promoter regions of DNA, namely "single GAS polymer model" and "double GAS polymer model" considering binding to single or double GAS sites, respectively. The length of DNA in the single GAS model was three sites and four sites in double GAS model. This model correspond to the "single GAS polymer model".
This model is described in the article:
STAT1-cooperative DNA binding distinguishes type 1 from type 2 interferon signaling.
Begitt A, Droescher M, Meyer T, Schmid CD, Baker M, Antunes F, Owen MR, Naumann R, Decker T, Vinkemeier U
Nat Immunol. 2014 Feb;15(2):168-76.
Abstract:
STAT1 is an indispensable component of a heterotrimer (ISGF3) and a STAT1 homodimer (GAF) that function as transcription regulators in type 1 and type 2 interferon signaling, respectively. To investigate the importance of STAT1-cooperative DNA binding, we generated gene-targeted mice expressing cooperativity-deficient STAT1 with alanine substituted for Phe77. Neither ISGF3 nor GAF bound DNA cooperatively in the STAT1F77A mouse strain, but type 1 and type 2 interferon responses were affected differently. Type 2 interferon-mediated transcription and antibacterial immunity essentially disappeared owing to defective promoter recruitment of GAF. In contrast, STAT1 recruitment to ISGF3 binding sites and type 1 interferon-dependent responses, including antiviral protection, remained intact. We conclude that STAT1 cooperativity is essential for its biological activity and underlies the cellular responses to type 2, but not type 1 interferon.
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2014-01-07 | BIOMD0000000500 | BioModels