TLR4 signaling of LPS chemotypes
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ABSTRACT:
PROVIDER: PRJNA1054506 | ENA |
REPOSITORIES: ENA
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Project description:TLR4 signaling of LPS chemotypes in THP-1 macrophages.
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Project description:TLR4 signaling of LPS chemotypes in HEK Blue hTLR4 reporter cells.
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Project description:The discovery of Toll-like receptors (TLRs) represented a significant breakthrough that paved the way for the study of host-pathogen interactions in innate immunity. However, there are still major gaps in understanding TLR function, especially the early dynamics of downstream TLR pathways remains less clear. We characterize a label-free optical biosensor-based assay as a powerful method to detect TLR activation in a native and label-free environment and to delineate the dynamics of TLR pathway activation. To gain a deeper insight into the biological processes underlying the ligand-specific signal traces of different LPS chemotypes in various cell types, RNA-seq analysis of transcriptional changes in THP-1 macropahges was performed. After 3 hours of stimulation with LPS E. coli or LPS S. minnesota, THP-1 macrophages showed significant changes in RNA expression compared to the unstimulated control.
2024-10-14 | GSE250544 | GEO
Project description:The discovery of Toll-like receptors (TLRs) represented a significant breakthrough that paved the way for the study of host-pathogen interactions in innate immunity. However, there are still major gaps in understanding TLR function, especially the early dynamics of downstream TLR pathways remains less clear. We characterize a label-free optical biosensor-based assay as a powerful method to detect TLR activation in a native and label-free environment and to delineate the dynamics of TLR pathway activation. To gain a deeper insight into the biological processes underlying the ligand-specific signal traces of different LPS chemotypes in various cell types, RNA-seq analysis of transcriptional changes in HEK Blue hTLR4 reporter cells was performed. After 3 hours of stimulation with LPS E. coli or LPS S. minnesota, HEK Blue hTLR4 reporter cells showed significant changes in RNA expression compared to the unstimulated control.
2024-10-14 | GSE250545 | GEO
Project description:The inflammatory mediator IL6 induced by LPS, which signals via TLR4, has been shown to feedback and augment TLR4 signaling when over-produced in LPS hypersensitive gp130F/F mice. The identity of the LPS/TLR4 responsive inflammatory signaling pathways and gene networks which are modulated by IL6 are unknown. Therefore, to understand the molecular consequences of gp130 hyperactivity in non-haemopoietic tissue on LPS-induced systemic inflammation, global gene expression profiling of livers was performed.
2011-05-17 | GSE29311 | GEO
Project description:The inflammatory mediator IL6 induced by LPS, which signals via TLR4, has been shown to feedback and augment TLR4 signaling when over-produced in LPS hypersensitive gp130F/F mice. The identity of the LPS/TLR4 responsive inflammatory signaling pathways and gene networks which are modulated by IL6 are unknown. Therefore, to understand the molecular consequences of gp130 hyperactivity in non-haemopoietic tissue on LPS-induced systemic inflammation, global gene expression profiling of livers was performed. The mouse 22K compugen oligo array from the Adelaide Microarray Facility was used to investigate the effect of LPS treatment on the livers of wildtype and gp130F/F mutant mice. Livers of both wildtype mice and gp130F/F mice at 6hr post LPS injection and also control livers wer collected. Each experimental group had 3 independant mice. In total 12 arrays were performed with a total of three biological replicates. A common reference design was used for this experiment. RNA extracted from eight pooled 17.5dpc C57BL/6 mouse embryos was used as the reference sample. 6 wildytpe mice and 6 gp130F/F mice were used in this study, with 3 mice of each genotype treated with LPS.
2011-05-17 | E-GEOD-29311 | biostudies-arrayexpress
Project description:Lipid A (a hexaacylated 1,4 bis-phosphate) is a potent immune stimulant for TLR4/MD-2. Upon lipid A ligation, the TLR4/MD-2 complex dimerizes and initiates signal transduction. Historically, studies also suggested the existence of TLR4/MD-2-independent LPS signaling. Here we define the role of TLR4 and MD-2 in LPS signaling by using genome wide expression profiling in TLR4- and MD-2-deficient macrophages after stimulations with peptidoglycan-free LPS and synthetic E.coli lipid A. Of the 1,396 genes found significantly induced or repressed by any one of the treatments in the wildtype macrophages, none was present in the TLR4- or MD-2-deficient macrophages, confirming that the TLR4/MD-2 complex is the only receptor for endotoxin, and are both absolutely required for responses to LPS. Using a molecular genetics approach, we investigated the mechanism of TLR4/MD-2 activation by combining the known crystal structure of TLR4/MD-2 with computer modeling. We used lipid IVa, a defined lipid A mimetic to model the activation of mouse TLR4/MD2. The two phosphates on lipid A were predicted to interact extensively with the two positively charged patches mouse TLR4 according to our dimeric murine TLR4/MD-2/lipid IVa model. These two patches are composed of K263, R337, and K360 (Positive Patch 1), and K367 and R434 (Positive Patch 2). When either Positive Patch was abolished by mutagenesis into Ala, the responses to LPS and lipid A were almost abrogated. Thus, ionic interactions between the two phosphates on lipid A and the two positively charged patches on murine TLR4 appear to be essential for LPS receptor activation.
2011-07-31 | GSE31066 | GEO
Project description:Lipid A (a hexaacylated 1,4 bis-phosphate) is a potent immune stimulant for TLR4/MD-2. Upon lipid A ligation, the TLR4/MD-2 complex dimerizes and initiates signal transduction. Historically, studies also suggested the existence of TLR4/MD-2-independent LPS signaling. Here we define the role of TLR4 and MD-2 in LPS signaling by using genome wide expression profiling in TLR4- and MD-2-deficient macrophages after stimulations with peptidoglycan-free LPS and synthetic E.coli lipid A. Of the 1,396 genes found significantly induced or repressed by any one of the treatments in the wildtype macrophages, none was present in the TLR4- or MD-2-deficient macrophages, confirming that the TLR4/MD-2 complex is the only receptor for endotoxin, and are both absolutely required for responses to LPS. Using a molecular genetics approach, we investigated the mechanism of TLR4/MD-2 activation by combining the known crystal structure of TLR4/MD-2 with computer modeling. We used lipid IVa, a defined lipid A mimetic to model the activation of mouse TLR4/MD2. The two phosphates on lipid A were predicted to interact extensively with the two positively charged patches mouse TLR4 according to our dimeric murine TLR4/MD-2/lipid IVa model. These two patches are composed of K263, R337, and K360 (Positive Patch 1), and K367 and R434 (Positive Patch 2). When either Positive Patch was abolished by mutagenesis into Ala, the responses to LPS and lipid A were almost abrogated. Thus, ionic interactions between the two phosphates on lipid A and the two positively charged patches on murine TLR4 appear to be essential for LPS receptor activation. Bone marrow-derived macrophages were pooled from four individual WT or TLR4-deficient mice and stimulated with either 10 ng LPS /mL, 100 ng lipid A/mL or 10 nM Pam2 for 2 hours and compared to PBS-stimulated control cells. We also compared PBS-stimulated WT cells directly to PBS-stimulated TLR4-deficient cells to compare the basal expression of genes in the two genotypes. This experiment was repeated once in its entirety.
2011-07-30 | E-GEOD-31066 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the SubSeries listed below.
2024-10-14 | GSE250546 | GEO
Project description:Toll-like receptor 4 (TLR4) sensing of lipopolysaccharide (LPS), the most potent pathogen-associated molecular pattern of gram-negative bacteria, activates NF-κB and Irf3, which induces inflammatory cytokines and interferons that trigger an intense inflammatory response, which is critical for host defense but can also cause serious inflammatory pathology, including sepsis. Although TLR4 inhibition is an attractive therapeutic approach for suppressing overexuberant inflammatory signaling, previously identified TLR4 antagonists have not shown any clinical benefit. Here, we identify disulfiram (DSF), an FDA-approved drug for alcoholism, as a specific inhibitor of TLR4-mediated inflammatory signaling. TLR4 cell surface expression, LPS sensing, dimerization and signaling depend on TLR4 binding to MD-2. DSF and other cysteine-reactive drugs, previously shown to block LPS-triggered inflammatory cell death (pyroptosis), inhibit TLR4 signaling by covalently modifying Cys133 of MD-2, a key conserved residue that mediates TLR4 sensing and signaling. DSF blocks LPS-triggered inflammatory cytokine, chemokine, and interferon production by macrophages in vitro. In the aggressive N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson’s disease (PD) in which TLR4 plays an important role, DSF markedly suppresses neuroinflammation and dopaminergic neuron loss, and restores motor function. Our findings identify a role for DSF in curbing TLR4-mediated inflammation and suggest that DSF and other drugs that target MD-2 might be useful for treating PD and other diseases in which inflammation contributes importantly to pathogenesis.
2023-08-07 | GSE237028 | GEO