Ontology highlight
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PROVIDER: PRJNA307977 | ENA |
REPOSITORIES: ENA
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Project description:Macrophages play a critical role in innate immunity, and the expression of early response genes orchestrate much of the initial response of the immune system. Macrophages undergo extensive transcriptional reprogramming in response to inflammatory stimuli such as Lipopolysaccharide (LPS). To identify gene transcription regulation patterns involved in early innate immune responses, we used two genome-wide approaches - gene expression profiling and chromatin immunoprecipitation-sequencing (ChIP-seq) analysis. We examined the effect of 2 hrs LPS stimulation on early gene expression and its relation to chromatin remodeling (H3 acetylation; H3Ac) and promoter binding of Sp1 and RNA polymerase II phosphorylated at serine 5 (S5P RNAPII), which is a marker for transcriptional initiation. Our results indicate novel and alternative gene regulatory mechanisms for certain proinflammatory genes. We identified two groups of up-regulated inflammatory genes with respect to chromatin modification and promoter features. One group, including highly up-regulated genes such as tumor necrosis factor (TNF), was characterized by H3Ac, high CpG content and lack of TATA boxes. The second group, containing inflammatory mediators (interleukins and CCL chemokines), was up-regulated upon LPS stimulation despite lacking H3Ac in their annotated promoters, which were low in CpG content but did contain TATA boxes. Genome-wide analysis showed that few H3Ac peaks were unique to either +/-LPS condition. However, within these, an unpacking/expansion of already existing H3Ac peaks was observed upon LPS stimulation. In contrast, a significant proportion of S5P RNAPII peaks (approx 40%) was unique to either condition. Furthermore, data indicated a large portion of previously unannotated TSSs, particularly in LPS-stimulated macrophages, where only 28% of unique S5P RNAPII peaks overlap annotated promoters. The regulation of the inflammatory response appears to occur in a very specific manner at the chromatin level for specific genes and this study highlights the level of fine-tuning that occurs in the immune response. 2 pairs of THP-1 cells either stimulated with LPS or not. ChIP using either H3K9/K14Ac, RNA Pol II (phospho S5) or SP1 antibody. This submission represents chip-seq component of study.
2012-03-07 | E-GEOD-32324 | biostudies-arrayexpress
Project description:Macrophages play a critical role in innate immunity, and the expression of early response genes orchestrate much of the initial response of the immune system. Macrophages undergo extensive transcriptional reprogramming in response to inflammatory stimuli such as Lipopolysaccharide (LPS). To identify gene transcription regulation patterns involved in early innate immune responses, we used two genome-wide approaches - gene expression profiling and chromatin immunoprecipitation-sequencing (ChIP-seq) analysis. We examined the effect of 2 hrs LPS stimulation on early gene expression and its relation to chromatin remodeling (H3 acetylation; H3Ac) and promoter binding of Sp1 and RNA polymerase II phosphorylated at serine 5 (S5P RNAPII), which is a marker for transcriptional initiation. Our results indicate novel and alternative gene regulatory mechanisms for certain proinflammatory genes. We identified two groups of up-regulated inflammatory genes with respect to chromatin modification and promoter features. One group, including highly up-regulated genes such as tumor necrosis factor (TNF), was characterized by H3Ac, high CpG content and lack of TATA boxes. The second group, containing inflammatory mediators (interleukins and CCL chemokines), was up-regulated upon LPS stimulation despite lacking H3Ac in their annotated promoters, which were low in CpG content but did contain TATA boxes. Genome-wide analysis showed that few H3Ac peaks were unique to either +/-LPS condition. However, within these, an unpacking/expansion of already existing H3Ac peaks was observed upon LPS stimulation. In contrast, a significant proportion of S5P RNAPII peaks (approx 40%) was unique to either condition. Furthermore, data indicated a large portion of previously unannotated TSSs, particularly in LPS-stimulated macrophages, where only 28% of unique S5P RNAPII peaks overlap annotated promoters. The regulation of the inflammatory response appears to occur in a very specific manner at the chromatin level for specific genes and this study highlights the level of fine-tuning that occurs in the immune response. 4 pairs of THP-1 cells either stimulated with LPS or not This submission represents transcriptome component of study.
2012-03-07 | E-GEOD-32141 | biostudies-arrayexpress
Project description:Activation of inflammation is tightly associated with metabolic reprogramming in macrophages. The iron-containing tetrapyrrole heme can induce pro-oxidant and pro-inflammatory effects in murine macrophages, but has been associated with polarization towards an anti-inflammatory phenotype in human macrophages. In the current study, we compared the regulatory responses to heme and the prototypical Toll-like receptor (TLR)4 ligand lipopolysaccharide (LPS) in human and mouse macrophages with a particular focus on alterations of cellular bioenergetics. In human macrophages, bulk RNA-sequencing analysis indicated that heme led to an anti-inflammatory transcriptional profile, whereas LPS induced a classical pro-inflammatory gene response. Co-stimulation of heme with LPS caused opposing regulatory patterns of inflammatory activation and cellular bioenergetics in human and mouse macrophages. Specifically, in LPS-stimulated murine, but not human macrophages, heme led to a marked suppression of oxidative phosphorylation and an up-regulation of glycolysis. The species-specific alterations in cellular bioenergetics and inflammatory responses to heme were critically dependent on the availability of nitric oxide (NO) that is generated in inflammatory mouse, but not human macrophages. Accordingly, studies with an inducible nitric oxide synthase (iNOS) inhibitor in mouse, and a pharmacological NO donor in human macrophages, reveal that NO is responsible for the opposing effects of heme in these cells. Taken together, the current findings indicate that NO is critical for the immunomodulatory role of heme in macrophages.
2024-05-13 | GSE255234 | GEO
Project description:A hallmark of immune-inflammatory responses is the generation of reactive oxygen and nitrogen species by innate immune cells, in particular macrophages. How macrophages cope with excess oxidant production and associated redox stress is not fully understood. Recent evidence implicates reactive sulfur species (RSS) in inflammatory responses, however, how RSS affect macrophage function and its ability to cope with oxidative-inflammatory stress remains poorly understood. Herein, we investigated endogenous pathways of RSS biogenesis and clearance in macrophages, and in particular, explored how hydrogen sulfide (H2S) and thiol persulidation influences macrophage oxidative-inflammatory response. We report that classical activation of mouse or human macrophages with lipopolysaccharide and interferon-γ (LPS/IFN-γ) triggers a marked production of H2S/RSS, leading to a widespread increase in protein persulfidation. Endogenous H2S/persulfidation levels were governed by the activity of the cystine importer xCT, the H2S-generating enzyme cystathionine γ-lyase and the sulfide-metabolizing enzyme sulfide quinone oxidoreductase (SQOR). High levels of H2S/persulfidation, observed upon LPS/IFN-γ stimulation or SQOR inhibition, were associated with a state of increased resistance to oxidative stress. Furthermore, enhanced persulfidation correlated with attenuated activation of the macrophage inflammasome and diminished inflammatory cell death. These findings shed light on the metabolism and effects of RSS in macrophages and point to an important role for persulfides in enabling macrophages to cope with oxidative-inflammatory stress.
2024-05-21 | PXD044043 | Pride
Project description:Macrophages and dendritic cells (DCs) differently contribute to the generation of coordinated immune system responses against infectious agents. They interact with microbes through germline-encoded pattern-recognition receptors (PRRs), which recognize molecular patterns expressed by various microorganisms. Upon antigen binding, PRRs instruct DCs for the appropriate priming of natural killer cells, followed by specific T-cell responses. Once completed the effector phase, DCs reach the terminal differentiation stage and eventually die by apoptosis. By contrast, following antigen recognition, macrophages initiate first the inflammatory process and then switch to an anti-inflammatory phenotype for the restoration of tissue homeostasis. Following lipopolysaccharide (LPS)-stimulation the initiation of the apoptotic pathway in DCs is due the activation of NFAT proteins. DC stimulation with lipopolysaccharide (LPS) induces Src-family kinase and phospholipase C (PLC)γ2 activation, influx of extracellular Ca2+ and calcineurin-dependent nuclear NFAT translocation. The initiation of this pathway is independent of TLR4 engagement, and dependent exclusively on CD14. We asked whether macrophage survival after LPS encounter was due to their inability to activate the Ca2+ pathway. As matter of fact, bone marrow-derived macrophages were unable to mobilize Ca2+ and to translocate NFAT to the. To further investigate whether the Ca2+-NFAT pathway played any role in LPS-stimulated macrophages, we performed a comparative kinetic microarray analysis in conditions allowing or inhibiting NFAT activation. We show here that no modulation of gene expression can be attributed to NFAT. Gene expression analyses were performed using Affymetrix GeneChips in the following groups of murine macrophaghes: 1) CD14-deficient macrophages stimulated with LPS; 2) wt macrophages stimulated with LPS in presence of EGTA; 3) wt macrophages stimulated with LPS. The following kinetic time points were examined: 0, 6 and 24 hours following LPS activation. This experimental setting allowed us to select for effects due to Ca2+ fluxes and exclude the effects due to other causes, particularly the block of TRIF recruitment in CD14-deficient cells and the EGTA effects unrelated to Ca2+ chelation.
2010-03-04 | E-GEOD-15721 | biostudies-arrayexpress
Project description:Macrophages play a critical role in innate immunity, and the expression of early response genes orchestrate much of the initial response of the immune system. Macrophages undergo extensive transcriptional reprogramming in response to inflammatory stimuli such as Lipopolysaccharide (LPS). To identify gene transcription regulation patterns involved in early innate immune responses, we used two genome-wide approaches - gene expression profiling and chromatin immunoprecipitation-sequencing (ChIP-seq) analysis. We examined the effect of 2 hrs LPS stimulation on early gene expression and its relation to chromatin remodeling (H3 acetylation; H3Ac) and promoter binding of Sp1 and RNA polymerase II phosphorylated at serine 5 (S5P RNAPII), which is a marker for transcriptional initiation. Our results indicate novel and alternative gene regulatory mechanisms for certain proinflammatory genes. We identified two groups of up-regulated inflammatory genes with respect to chromatin modification and promoter features. One group, including highly up-regulated genes such as tumor necrosis factor (TNF), was characterized by H3Ac, high CpG content and lack of TATA boxes. The second group, containing inflammatory mediators (interleukins and CCL chemokines), was up-regulated upon LPS stimulation despite lacking H3Ac in their annotated promoters, which were low in CpG content but did contain TATA boxes. Genome-wide analysis showed that few H3Ac peaks were unique to either +/-LPS condition. However, within these, an unpacking/expansion of already existing H3Ac peaks was observed upon LPS stimulation. In contrast, a significant proportion of S5P RNAPII peaks (approx 40%) was unique to either condition. Furthermore, data indicated a large portion of previously unannotated TSSs, particularly in LPS-stimulated macrophages, where only 28% of unique S5P RNAPII peaks overlap annotated promoters. The regulation of the inflammatory response appears to occur in a very specific manner at the chromatin level for specific genes and this study highlights the level of fine-tuning that occurs in the immune response.
2012-03-07 | GSE32324 | GEO
Project description:Tight regulation of Toll-like receptor (TLR)-mediated inflammatory responses is important in innate immunity. Here, we show that T cell death-associated gene 51 (TDAG51/PHLDA1) is a novel coactivator of the transcription factor FoxO1, regulating inflammatory mediator production in the lipopolysaccharide (LPS)-induced inflammatory response. TDAG51 induction by LPS stimulation was mediated by the TLR2/4 signaling pathway in bone marrow-derived macrophages (BMMs). LPS-induced inflammatory mediator production was significantly decreased in TDAG51-deficient BMMs. In TDAG51-deficient mice, LPS- or pathogenic Escherichia coli infection-induced lethal shock was reduced by decreasing serum proinflammatory cytokine levels. The recruitment of 14-3-3 to FoxO1 was competitively inhibited by the TDAG51-FoxO1 interaction, leading to blockade of FoxO1 cytoplasmic translocation and thereby strengthening FoxO1 nuclear accumulation. TDAG51/FoxO1 double-deficient BMMs showed significantly reduced inflammatory mediator production compared with TDAG51- or FoxO1-deficient BMMs. TDAG51/FoxO1 double deficiency protected mice against LPS- or pathogenic E. coli infection-induced lethal shock by weakening the systemic inflammatory response. Thus, these results indicate that TDAG51 acts as a coactivator of the transcription factor FoxO1, leading to strengthened FoxO1 activity in the LPS-induced inflammatory response.
2023-06-24 | PXD039815 | Pride
Project description:In autoimmune diseases, accumulation of activated leukocytes correlates with inflammation and disease progression, and therefore, disruption of leukocyte trafficking is an active area of research. The protein kinase Tpl2 (MAP3K8) regulates leukocyte inflammatory responses and is also being investigated for therapeutic inhibition during autoimmunity. Herein, we addressed the contribution of Tpl2 to the regulation of macrophage chemokine and chemokine receptor expression and subsequent migration in vivo using a mouse model of Tpl2 ablation. We found that gene expression of the chemokine ligands CCL2, CCL7, CXCL2, and CXCL3 as well as the chemokine receptors CCR1 and CCR5 were reduced in macrophages from the bone marrow and peritoneal cavities of tpl2-/- mice following stimulation with LPS. LPS stimulation repressed chemokine receptor expression of CCR1, CCR2 and CCR5. Notably, LPS-induced repression of CCR1 and CCR5 was significantly enhanced in Tpl2-deficient macrophages and was observed to be dependent upon Erk activation and independent of PI3K and mTOR signaling. Consistent with alterations in chemokine and chemokine receptor expression, tpl2-/- macrophages were defective in trafficking to the peritoneal cavity following thioglycollate-induced inflammation. Overall, this study demonstrates a Tpl2-dependent mechanism for macrophage expression of both chemokine receptors and their ligands and provides further insight into how Tpl2 inhibition may disrupt inflammatory networks in vivo. microarray was used to profile the genome-wide expression patterns in Tpl2 wild-type and deficient macrophage.
2014-06-03 | E-GEOD-48338 | biostudies-arrayexpress
Project description:Macrophages are a major cellular component of all inflammatory situations, generating proinflammatory cytokines such as TNF-alpha, IL-1, and IL-6 that are central to the initiation and maintenance of inflammation. To determine whether the tumor suppressor ARF plays a role in inflammatory gene expression, we used an 84-gene RT2 PCR array to examine the expression of inflammation-associated genes in WT and ARF-deficient macrophages treated with the TLR4 ligand LPS. Peritoneal macrophages from WT and ARF-deficient mice were obtained and treated with LPS (200ng/ml) for 4 hours. WT control (without stimulation n=4), WT LPS (n=4), ARF Control (n=4), ARF LPS (n=4)
2011-09-29 | E-GEOD-32446 | biostudies-arrayexpress
Project description:Macrophages are crucial in controlling infectious agents and tissue homeostasis. Macrophages require a wide range of functional capabilities in order to fulfill distinct roles in our body, one being rapid and robust immune responses. To gain insight into macrophage plasticity and the key regulatory protein networks governing their specific functions, we performed quantitative analyses of the proteome and phosphoproteome of murine primary GM-CSF and M-CSF grown bone marrow derived macrophages (GM-BMMs and M-BMMs, respectively) using the latest isobaric tag based tandem mass tag (TMT) labeling and liquid chromatography-tandem mass spectrometry (LC-MS/MS). Strikingly, metabolic processes emerged as a major difference between these macrophages. Specifically, GM-BMMs show significant enrichment of proteins involving glycolysis, the mevalonate pathway, and nitrogen compound biosynthesis. This evidence of enhanced glycolytic capability in GM-BMMs is particularly significant regarding their pro-inflammatory responses, because increased production of cytokines upon LPS stimulation in GM-BMMs depends on their acute glycolytic capacity. In contrast, M-BMMs upregulate proteins involved in endocytosis, which correlates with a tendency toward homeostatic functions such as scavenging cellular debris. Together, our data describes a proteomic network that underlies the pro-inflammatory actions of GM-BMMs as well as the homeostatic functions of M-BMMs.
2015-08-04 | PXD002582 | Pride