Homo sapiens
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PROVIDER: PRJNA338182 | ENA |
REPOSITORIES: ENA
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Project description:The direct communication between our central nervous and inflammatory signalling systems is a well-recognised, yet poorly understood relationship. To increase our understanding of this relationship, we examined the metabolism of serotonin and its precursor tryptophan in macrophages under inflammatory settings. Both are involved in inflammatory signalling and known to play a major role in mood regulation. Tryptophan depletion by macrophages during inflammation can consequently result in a reduction of serotonin systemically and has been suggested to cause depression. Increased understanding of this system could help overcome the problem of treatment resistant depressed patients. To this end, we treated primary human monocyte derived macrophages with a range of anti-depressant/anti-inflammatory drugs and analysed their transcriptional profile under various inflammatory conditions. In addition to the classic endotoxic driver of inflammation, LPS, we also used IFNα which is a constitutive cytokine shown to directly induce depression when administered in high doses. The anti-depressant drugs were not found to have any significant effects on macrophage inflammatory signalling. However, the anti-inflammatories drugs were found to alter components of the serotonin/tryptophan metabolism pathways. This study increases our understanding of the intricacies of immune/mood cross-talk and offers into developing anti-inflammatories as co-treatment for depression. We treated human primary macrophage cells with anti-inflammatory or anti-depressant drugs and analysed their transcriptional effects during inf.lammatory signaling within the context of tryptophan metabolism/kynurenic metabolism.
2018-01-01 | GSE85333 | GEO
Project description:We report that a high affinity, selective, small molecule Gpr120 agonist (cpdA), exerts potent anti-inflammatory effects on macrophages in vitro, and in obese mice in vivo. Gpr120 agonist treatment of high fat diet (HFD)/obese mice causes improved glucose tolerance, decreased hyperinsulinemia, increased insulin sensitivity and decreased hepatic steatosis. This suggests that Gpr120 agonists could become new insulin sensitizing drugs for the treatment of Type 2 diabetes and other human insulin resistant states in the future. Examination of effects of DHA and compound A on primary macrophages stimulated by LPS, 3 replicates for each condition
2014-06-07 | E-GEOD-58282 | biostudies-arrayexpress
Project description:Macrophages are key immune cells in tissues that are able to adapt their metabolic phenotype in response to different stimuli. Lysine deacetylases are important enzymes for regulating inflammatory gene expression and their inhibitors have anti-inflammatory effects in models of chronic obstructive pulmonary disease (COPD). We hypothesized that these anti-inflammatory effects may be driven by or associated with metabolic changes in macrophages. To validate this hypothesis, we used an unbiased and a targeted proteomic approach to investigate metabolic enzymes and LC- and GC-MS to quantify metabolites in combination with functional parameters in primary murine alveolar-like macrophages after lipopolysaccharide (LPS)-induced activation with and without lysine deacetylase inhibitors. We found that lysine deacetylase inhibitor treatment resulted in reduced production of inflammatory mediators such as TNF-α and IL-1β. However, only minor changes in macrophage metabolism were observed, as only one of the deacetylase inhibitors slightly increased mitochondrial respiration. However, lysine deacetylase inhibition specifically enhanced expression of proteins involved in ubiquitination, and this may be a potential driver of the anti-inflammatory effects of lysine deacetylase inhibitors. Our data illustrate that a multi-omics approach is necessary to gain a better understanding of how macrophages interact with cues from their environment. More detailed insight into the molecular mechanisms of KDAC inhibition is needed and investigating ubiquitination seems a promising next step. This is important as conventional anti-inflammatory drugs like corticosteroids have low effectiveness in many patients and novel therapeutic strategies are urgently needed.
2024-02-21 | PXD040933 | Pride
Project description:Glucocorticoids are widely prescribed anti-inflammatory drugs with tissue-specific effects. Beneficial anti-inflammatory effects are caused in cells of the immune system whereas metabolic adverse effects of glucocorticoid therapy are seen in metabolic tissues such as liver. The glucocorticoid receptor (GR), a nuclear receptor targeted by glucocorticoids, bind its DNA response elements upon ligand exposure in a tissue-specific manner. Tissue-specific GR binding patterns depend on the access of its binding sites, which determines the tissue-specific glucocorticoid response. Here, we investigated this response by nascent RNAseq in murine bone marrow-derived macrophages (BMDMs) after stimulation with lipopolysaccharide (LPS) and dexamethasone (Dex). After labelling newly synthesized transcripts with 4-thiouracile (4sU), we identified macrophage-specific non-coding transcripts expressed at intergenic GR binding sites. Those transcripts are regulated by the GR and correlate with its anti-inflammatory function in macrophages. Those findings add another layer to the mechanisms underpinning GR's tissue-specific gene regulation and represent potential drug targets in anti-inflammatory therapy and/or management of adverse effects in glucocorticoid therapy.
2021-12-31 | GSE186629 | GEO
Project description:Peripheral serotonin (5-HT) exacerbates or limits inflammatory pathologies (pulmonary arterial hypertension, cardiac valve degeneration, systemic sclerosis, gut disorders, neuroendocrine neoplasms, arthritis) through interaction with seven types of 5-HT receptors (5-HT1-7). As central regulators of inflammation, macrophages are critical targets of 5-HT, which promotes their anti-inflammatory and pro-fibrotic polarization primarily via the 5-HT7-Protein Kinase A (PKA) axis. However, anti-inflammatory human macrophages are also characterized by the expression of 5-HT2B, an off-target of anesthetics, anti-parkinsonian drugs and Selective Serotonin Reuptake Inhibitors (SSRI) that contributes to 5-HT-mediated pathologies. Since 5-HT2B prevents mononuclear phagocyte degeneration in amyotrophic lateral sclerosis and modulates motility of murine microglial processes, we sought to determine the functional and transcriptional consequences of 5-HT2B activation in human macrophages. Ligation of 5-HT2B by the 5-HT2B-specific agonist BW723C86, which exhibits antidepressant- and anxiolytic-like effects in animal models, significantly modified the cytokine profile and the transcriptional signature in macrophages. Importantly, 5-HT2B agonist-induced transcriptional changes were partly mediated through activation of the Aryl hydrocarbon Receptor (AhR), a ligand-dependent transcription factor that regulates immune responses and the biological responses to xenobiotics. Besides, BW723C86 triggered transcriptional effects that could not be abrogated by 5-HT2B antagonists and impaired monocyte-to-osteoclast differentiation. Therefore, our results demonstrate the existence of a functional 5-HT2B-AhR link in human macrophages and indicate that the commonly used 5-HT2B agonist BW723C86 exhibits 5-HT2B-independent effects.
2019-09-17 | GSE121825 | GEO
Project description:MAFB controls the transcriptional profile of human anti-inflammatory macrophages
| PRJNA330676 | ENA
Project description:Glucocorticoids represent the mainstay of therapy for a broad spectrum of immune-mediated inflammatory diseases (IMIDs). However, molecular mechanisms underlying their anti inflammatory mode of action have remained incompletely understood. Here we show that the anti-inflammatory properties of glucocorticoids involve a reprogramming of the mitochondrial metabolism of macrophages, which results in an increased and sustained production of the anti-inflammatory metabolite itaconate and a consequent inhibition of the inflammatory response. The glucocorticoid receptor interacts with parts of the pyruvate dehydrogenase complex where glucocorticoids provoke an increase in activity and allow an accelerated and paradoxical flux of the tricarboxylic acid (TCA) cycle in otherwise pro-inflammatory macrophages. This glucocorticoid-mediated rewiring of mitochondrial metabolism potentiates TCA cycle-dependent production of itaconate throughout the inflammatory response, thereby interfering with the production of pro-inflammatory cytokines. Artificial block of the TCA cycle or genetic deficiency in aconitate decarboxylase 1, the rate-limiting enzyme of itaconate synthesis, in contrast, interferes with the anti-inflammatory effects of glucocorticoids and accordingly abrogates their beneficial effects during a diverse range of preclinical models of IMIDs. Our findings provide important additional insights into the anti-inflammatory properties of glucocorticoids and have substantial implications for the future design of novel classes of anti-inflammatory drugs.
2024-02-19 | GSE250274 | GEO
Project description:Glucocorticoids represent the mainstay of therapy for a broad spectrum of immune-mediated inflammatory diseases (IMIDs). However, molecular mechanisms underlying their anti inflammatory mode of action have remained incompletely understood. Here we show that the anti-inflammatory properties of glucocorticoids involve a reprogramming of the mitochondrial metabolism of macrophages, which results in an increased and sustained production of the anti-inflammatory metabolite itaconate and a consequent inhibition of the inflammatory response. The glucocorticoid receptor interacts with parts of the pyruvate dehydrogenase complex where glucocorticoids provoke an increase in activity and allow an accelerated and paradoxical flux of the tricarboxylic acid (TCA) cycle in otherwise pro-inflammatory macrophages. This glucocorticoid-mediated rewiring of mitochondrial metabolism potentiates TCA cycle-dependent production of itaconate throughout the inflammatory response, thereby interfering with the production of pro-inflammatory cytokines. Artificial block of the TCA cycle or genetic deficiency in aconitate decarboxylase 1, the rate-limiting enzyme of itaconate synthesis, in contrast, interferes with the anti-inflammatory effects of glucocorticoids and accordingly abrogates their beneficial effects during a diverse range of preclinical models of IMIDs. Our findings provide important additional insights into the anti-inflammatory properties of glucocorticoids and have substantial implications for the future design of novel classes of anti-inflammatory drugs.
2024-02-19 | GSE250273 | GEO
Project description:Anti-Inflammatory Effects of Budesonide in Human Fetal Lung
| PRJNA327261 | ENA
Project description:Inflammatory responses triggered by either microbial or endogenous stimuli rely on a complex transcriptional program that involves the differential expression of hundreds of genes. Jmjd3, a JmjC family histone demethylase (HDM), is quickly induced by the transcription factor NF-kB in response to inflammatory stimuli. Jmjd3 erases a histone mark associated with transcriptional repression and silencing, trimethylated lysine 27 in histone H3 (H3K27me3). Thus, Jmjd3-mediated demethylation of H3K27me3 links inflammation to the control of a histone modification involved in lineage determination, differentiation and tissue homeostasis. However, the specific contribution of Jmjd3 induction to innate immunity and inflammation remains unknown. Here we combined genome-wide mapping and gene knockout studies to investigate this issue. Chromatin immunoprecipitation (ChIP) coupled to ultra high-throughput sequencing (ChIP-Seq) in LPS-stimulated primary mouse macrophages demonstrated that Jmid3 is recruited to a large number of genomic targets with a strong preference for active transcription start sites (TSS). Virtually all Jmjd3-bound TSSs were characterized by high levels of H3K4me3, a marker of gene activity, and high levels of RNA polymerase II (Pol_II). Inducible genes showing a strong increase in H3K4me3 and Pol_II recruitment after endotoxin treatment (including those encoding several cytokines, chemokines and antiviral proteins) were in most cases Jmjd3-associated. In Jmjd3-knockout macrophages, initial RNA_Pol II recruitment and activation of Jmjd3 target genes was unaffected, but RNA_Pol II was prematurely released, thus resulting in non-sustained responses. Importantly, most Jmjd3 target genes were not associated with detectable levels of H3K27me3, and transcriptional effects of Jmjd3 absence in the window of time analyzed here were uncoupled from measurable effects on this histone mark. Our data indicate that Jmjd3 is the effector of an NF-kB-controlled feed-forward transcriptional loop pervasively sustaining inflammatory transcriptional responses in a manner that is independent of H3K27me3 demethylation, and suggest the possible use of anti-Jmjd3 drugs to dampen pathologic inflammation. Keywords: Epigenetics Genome wide maps of histone demethylase jmjd3, the histone marks H3K4me3 and H3K27me3, and RNA-Polymerase II induction in mouse bone marrow-derived macrophages of two types: (a) untreated and (b) stimulated with lipopolysaccharide and interferon gamma to produce an inflammatory response.
2009-11-23 | E-GEOD-17631 | biostudies-arrayexpress