Transcriptional profiling of liver from mice treated with Toll-like receptor 5 agonists
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ABSTRACT:
PROVIDER: PRJNA687421 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13292641_1.fastq.gz | Fastqsanger.gz | |||
| SRR13292641_2.fastq.gz | Fastqsanger.gz | |||
| SRR13292642_1.fastq.gz | Fastqsanger.gz | |||
| SRR13292642_2.fastq.gz | Fastqsanger.gz | |||
| SRR13292643_1.fastq.gz | Fastqsanger.gz |
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Project description:Entolimod, a pharmacological derivative of the natural Toll-like receptor 5 (TLR5) agonist flagellin, has strong therapeutic potential for several indications including radioprotection and cancer immunotherapy. However, in Phase 1 studies, entolimod induced a rapid neutralizing immune response, presumably due to flagellin-reactive immune memory derived from life-long exposure of adult humans to flagellated enterobacteria. Since applications requiring repeated dosing could be precluded by entolimod’s neutralizing antigenicity and immunogenicity, we used structure-guided reengineering to develop a new, substantially deimmunized entolimod variant, GP532. We used RNAseq-based analysis of global gene expression profiles in C57BL/6 mice following systemic administration of entolimod vs GP532 to evaluate the biocomparability of the two drugs. In this experiment, we used wild type (WT) and TLR5-/- mice (on the same genetic background) to address the TLR5-dependence/specificity of responses and focused on the liver since it was previously defined as the major organ responsive to TLR5 systemic administration in mice . Analysis of livers collected 30 minutes after injection of entolimod or GP532 was aimed at assessing direct primary TLR5 responses, while a 24-hour time point was included (for wild type mice) to define long-term overall (direct and indirect) effects of TLR5 activation. Overall, our RNAseq-based analysis of the effects of entolimod and GP532 on transcription confirmed our expectations of their mechanism of action and overall biocomparability. These results establish GP532 as a highly optimized TLR5 agonist suitable for multi-dose therapeutic regimens and for patients with high titers of preexisting flagellin-neutralizing antibodies.
2020-12-24 | GSE163748 | GEO
Project description:Acute liver failure (ALF) is a severe consequence of abrupt hepatocyte injury with lethal outcomes. Three toll-like receptor (TLR) agonists, including polyinosinic-polycytidylic acid [poly(I:C)], lipopolysaccharide (LPS), and cytosine-phosphate-guanine oligonucleotide (CpG ODN), respectively, cause severe and acute hepatitis in D-galactosamine (D-GalN) sensitized mice as the experimental ALF animal models. However, the molecular differences in ALF among the three models are unclear. Here, we conducted global proteomic analyses of the three ALF mice models. We identified 227, 321, and 114 differentially regulated proteins and 80,195, and 23 specifically expressed proteins in the poly(I:C)/D-GalN, LPS/D-GalN and CpG ODN/D-GalN groups compared to the control group, respectively. Fifty-two proteins were commonly identified in the three ALF groups. Gene ontology (GO) analyses showed that 45 proteins were located in organelles, 35 proteins were involved in metabolic processes, and 10 proteins were involved in immune system processes. Poly (I:C)- and LPS-specific proteins were mainly distributed in the membrane and endoplasmic reticulum, respectively. LPS-specific proteins were more enriched in metabolic pathways. CpG-specific proteins were mainly related to the ribosome structural composition. In conclusion, our study shows different molecular mechanisms of three TLR agonists in D-GalN induced ALF and provides a useful dataset for the guidance of future studies.
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Project description:Goal of the experiment was to examine the effects of different Toll-like receptor agonists on the human astrocyte response, in termsof levels of transcripts encoding cytokines, chemokines and theirreceptors. Stathmin and poly IC are considered as agonist for TLR3, LPSas an agonist for TLR4. The manuscript we are about to submit to Journal of Immunology contains these data, and identifies stathmin, aprotein, as a novel TLR3 agonist. We all know that poly IC is, and bycomparing the transcript responses in astrocytes to either poly IC andstathmin, and observing the similarity in these responses, the experiment adds to the evidence that stathmin indeed activates a verysimilar cellular response as poly IC. The LPS-induced response,mediated by TLR4, is included as a reference, to illustrate thatanother TLR-mediated reaction produces quite something different.
2010-02-11 | E-TABM-851 | biostudies-arrayexpress
Project description:When macrophages are activated by sensing bacterial lipopolysaccharides (LPS), they greatly increase their motility, mRNA synthesis and protein production. Most of the ATP needed for these responses is derived from the uptake and catabolism of glucose, a relatively inefficient ATP source. Although the stimulated cells also increase their uptake of free fatty acids, they store a large fraction as triglycerides (TAG). We report here that both Toll-like receptor 4 (TLR4) and TLR2 agonists stimulate prolonged TAG retention by primary murine and human macrophages. Agonist-induced TAG storage lasted at least 72-96 hrs in vitro and was associated with increases in fatty acid (FA) uptake, FA esterification, and FA incorporation into TAG; FA oxidation decreased. The results of expression and inhibitor studies support a prominent role for increases in long chain acyl CoA synthase 1 (ACSL1) and diacylglycerol acyltransferase-2 (DGAT2) during the sustained response to TLR2/4 activation; decreases in adipose triglyceride lipase (ATGL, Pnpla2) and monoacylglycerol lipase (MgII) may also contribute. Stimulated murine macrophages that retained TAG carried out phagocytosis more effectively and were protected from saturated fatty acid-induced cell death (lipotoxicity). TLR agonist-induced TAG retention in macrophages is thus an active, sustained process that may have important adaptive functions. It may also contribute to the persistence of lipid-laden macrophages in infected tissues, host susceptibility to some microbial pathogens, and the pathogenesis of atherosclerosis. RNA from macrophage loaded with Fatty Acids, stimulated with bacterial lipopolysaccharides (LPS), or both compared to untreated controls (FA, LPS, FA+LPS, untreated). Replicates from 4 independent experiments.
2013-12-17 | E-GEOD-42190 | biostudies-arrayexpress
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Project description:When macrophages are activated by sensing bacterial lipopolysaccharides (LPS), they greatly increase their motility, mRNA synthesis and protein production. Most of the ATP needed for these responses is derived from the uptake and catabolism of glucose, a relatively inefficient ATP source. Although the stimulated cells also increase their uptake of free fatty acids, they store a large fraction as triglycerides (TAG). We report here that both Toll-like receptor 4 (TLR4) and TLR2 agonists stimulate prolonged TAG retention by primary murine and human macrophages. Agonist-induced TAG storage lasted at least 72-96 hrs in vitro and was associated with increases in fatty acid (FA) uptake, FA esterification, and FA incorporation into TAG; FA oxidation decreased. The results of expression and inhibitor studies support a prominent role for increases in long chain acyl CoA synthase 1 (ACSL1) and diacylglycerol acyltransferase-2 (DGAT2) during the sustained response to TLR2/4 activation; decreases in adipose triglyceride lipase (ATGL, Pnpla2) and monoacylglycerol lipase (MgII) may also contribute. Stimulated murine macrophages that retained TAG carried out phagocytosis more effectively and were protected from saturated fatty acid-induced cell death (lipotoxicity). TLR agonist-induced TAG retention in macrophages is thus an active, sustained process that may have important adaptive functions. It may also contribute to the persistence of lipid-laden macrophages in infected tissues, host susceptibility to some microbial pathogens, and the pathogenesis of atherosclerosis.
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Project description:The nuclear receptor PPARalpha is recognized as the primary target of the fibrate class of hypolipidemic drugs and mediates lipid lowering in part by activating a transcriptional cascade that induces genes involved in the catabolism of lipids. We report here the characterization of three novel PPARalpha agonists with therapeutic potential for treating dyslipidemia. These structurally related compounds display potent and selective binding to human PPARalpha and support robust recruitment of coactivator peptides in vitro. These compounds markedly potentiate chimeric transcription systems in cell-based assays and strikingly lower serum triglycerides in vivo. The transcription networks induced by these selective PPARalpha agonists were assessed by transcriptional profiling of mouse liver after acute and chronic treatment. The induction of several known PPARalpha target genes involved with fatty acid metabolism were observed, reflecting the expected pharmacology associated with PPARalpha activation. We also noted the downregulation of a number of genes related to immune cell function, the acute phase response, and glucose metabolism; suggesting that these compounds may have anti-inflammatory action in the mammalian liver. Taken together, these studies articulate the therapeutic promise of a selective PPARalpha agonist. Experiment Overall Design: Male C57Bl/6 mice (n=4 for all except 5 day treatment of 146-02 was n=2) were treated with the piperidine agonists for 24hr or 5 days at 1mg/kg/day, or water (vehicle) as control.
2008-12-02 | E-GEOD-12147 | biostudies-arrayexpress
Project description:To test whether dendritic cells from patient-derived tumor digests can be activated by agonists and which genes are regulated, we performed a single-cell RNA-seq of immune cells (CD45+) from 4 donors.
2022-06-15 | E-MTAB-11734 | biostudies-arrayexpress
Project description:The nuclear receptor PPARalpha is recognized as the primary target of the fibrate class of hypolipidemic drugs and mediates lipid lowering in part by activating a transcriptional cascade that induces genes involved in the catabolism of lipids. We report here the characterization of three novel PPARalpha agonists with therapeutic potential for treating dyslipidemia. These structurally related compounds display potent and selective binding to human PPARalpha and support robust recruitment of coactivator peptides in vitro. These compounds markedly potentiate chimeric transcription systems in cell-based assays and strikingly lower serum triglycerides in vivo. The transcription networks induced by these selective PPARalpha agonists were assessed by transcriptional profiling of mouse liver after acute and chronic treatment. The induction of several known PPARalpha target genes involved with fatty acid metabolism were observed, reflecting the expected pharmacology associated with PPARalpha activation. We also noted the downregulation of a number of genes related to immune cell function, the acute phase response, and glucose metabolism; suggesting that these compounds may have anti-inflammatory action in the mammalian liver. Taken together, these studies articulate the therapeutic promise of a selective PPARalpha agonist. Keywords: acute versus chronic treatment of piperidine PPARalpha agonists
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