Intestinal epithelial TLR4 signaling affects microbial invasion, epithelial function, and causes transmissible colitis
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ABSTRACT:
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR713610_1.fastq.gz | Fastqsanger.gz | |||
| ERR713610_2.fastq.gz | Fastqsanger.gz | |||
| ERR713611_1.fastq.gz | Fastqsanger.gz | |||
| ERR713611_2.fastq.gz | Fastqsanger.gz | |||
| ERR713612_1.fastq.gz | Fastqsanger.gz |
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Project description:Evidence obtained from gene knockout studies supports the role of Toll-like receptor 4 (TLR4) in intestinal inflammation and microbiota recognition. Increased epithelial TLR4 expression is observed in patients with inflammatory bowel disease. However, little is known of the effect of increased TLR4 signaling on intestinal homeostasis. Here, we examined the effect of increased TLR4 signaling on epithelial function and microbiota by using transgenic villin-TLR4 mice that overexpress TLR4 in the intestinal epithelium. Our results revealed that villin-TLR4 mice are characterized by increases in the density of mucosa-associated bacteria and bacterial translocation. Furthermore, increased epithelial TLR4 signaling was associated with an impaired epithelial barrier, altered expression of antimicrobial peptide genes, and altered epithelial cell differentiation. The composition of the colonic luminal and mucosa-associated microbiota differed between villin-TLR4 and wild-type (WT) littermates. Interestingly, WT mice cohoused with villin-TLR4 mice displayed greater susceptibility to acute colitis than singly housed WT mice did. The results of this study suggest that epithelial TLR4 expression shapes the microbiota and affects the functional properties of the epithelium. The changes in the microbiota induced by increased epithelial TLR4 signaling are transmissible and exacerbate dextran sodium sulfate-induced colitis. Together, our findings imply that host innate immune signaling can modulate intestinal bacteria and ultimately the host's susceptibility to colitis.
| S-EPMC4771346 | biostudies-literature
Project description:Abstract. Background: The cause of ulcerative colitis (UC) is not yet fully understood. Previous research has pointed towards a potential role for mutations in NOD2 in promoting the onset and progression of inflammatory bowel disease (IBD) by altering the microbiota of the gut. However, the relationship between toll-like receptor 4 (TLR4) and gut microbiota in IBD is not well understood. To shed light on this, the interaction between TLR4 and gut microbiota was studied using a mouse model of IBD. Methods: To examine the function of TLR4 signaling in intestinal injury repair, researchers developed Dextran Sulfate Sodium Salt (DSS)-induced colitis and injury models in both wild-type (WT) mice and TLR4 knockout (TLR4-KO) mice. To assess changes in the gut microbiota, 16S rRNA sequencing was conducted on fecal samples from both the TLR4-KO and WT enteritis mouse models. Results: The data obtained depicted a protective function of TLR4 against DSS-induced colitis. The gut microbiota composition was found to vary considerably between the WT and TLR4-KO mice groups as indicated by β-diversity analysis and operational taxonomic units (OTUs) cluster. Statistical analysis of microbial multivariate variables depicted an elevated abundance of Escherichia coli/Shigella, Gammaproteobacteria, Tenerlcutes, Deferribacteres, Enterobacteria, Rikenellaceae, and Proteobacteria in the gut microbiota of TLR4-KO mice, whereas there was a considerable reduction in Bacteroidetes at five different levels of the phylogenetic hierarchy including phylum, class, order, family, and genus in comparison with the WT control. Conclusion: TLR4 may protect intestinal epithelial cells from damage in response to DSS-induced injury by controlling the microbiota in the gut.
2023-11-01 | GSE227565 | GEO
Project description:The model was constructed to describe TLR4 induced NF-κB activation in native bone marrow-derived macrophages. It included processes of ligand (lipopolysaccharide) recognition, formation of dimer receptor complex and further signal transduction through TRAF6/TAK1 complex that leads to the activation of IKKα/β kinase, which in turn enables the NF-κB transcription factor phosphorylation and translocation in the cell nucleus, and induction of IkB and WIP1 (as an example of induced protein that promotes NF-κB dephosphorylation 2) gene transcription. Models were based on the current knowledge of TLR signaling framework, protein interactions within the TLR4 pathway, and up-to-date mathematical models describing Toll receptor activation.
The major important additions were made to TLR4 signaling description:
1) Receptor dimerization process
2) The existence of a basal nuclear NF-κB level (translocation)
3) NF-κB phosphorylation by IKK complex
2019-03-27 | MODEL1809230001 | BioModels
Project description:We show that oxidized LA, rather than LA itself,exacerbates colitis via Toll-like receptor 4 (TLR4)- and gut microbiota-dependent mechanisms.Administration of a diet containing oxidized LA, at low human-consumption levels, increases the severity of colitis and exacerbates the development of colorectal tumorigenesis in mice.
2023-12-31 | GSE209580 | GEO
Project description:The toll-like receptor 4 (TLR4) is a central regulator of innate immune signaling that primarily recognizes bacterial lipopolysaccharide (LPS) cell wall constituents to trigger cytokine secretion. We identify the intramembrane protease RHBDL4 as a negative regulator of TLR4 signaling. We show that RHBDL4-triggers the degradation of TLR4’s trafficking factor TMED7, a member of the p24 family of COPII adaptor proteins, which counteracts the transport of TLR4 to the cell surface. Besides TMED7, RHBDL4 cleaves a subset of related p24 cargo receptors, suggesting that this is a general protein abundance control mechanism to regulate the loading of specific secretory proteins into COPII vesicles. Notably, TLR4 activation by LPS mediates transcriptional upregulation of RHBDL4. Hence, TLR4 activation triggers an RHBDL4-dependent negative feedback loop to reduce the export of newly synthesized TLR4 molecules from the endoplasmic reticulum into COPII-coated vesicles. This secretory cargo tuning mechanism prevents the over-activation of TLR4-dependent signaling and consequently alleviates septic shock in a mouse model.
2024-01-09 | PXD045934 | Pride
Project description:Villin-TLR4 mice and their wild-type littermates underwent the AOM-DSS model of tumorigenesis and their non-involved tissues were analyzed for transcriptomic expression
2020-01-01 | GSE141767 | GEO
Project description:Use of human whole blood for transcriptomic analysis has potential advantages over the use of isolated immune cells for studying the transcriptional response to pathogens and their products. Whole blood stimulation can be carried out in a laboratory without the expertise or equipment to isolate immune cells from blood, with the added advantage of being able to undertake experiments using very small volumes of blood. Toll like receptors (TLRs) are a family of pattern recognition receptors which recognise highly conserved microbial products. Using the TLR2 ligand (Pam3CSK4) and the TLR4 ligand (LPS) human whole blood was stimulated for 0, 1, 3, 6, 12 or 24 hours at which times mRNA was isolated and a comparative microarray was undertaken. A common NFκB transcriptional programme was identified following both TLR2 and TLR4 ligation which peaked at between 3 to 6 hours including upregulation of many of the NFκB family members. In contrast an interferon transcriptional response was observed following TLR4 but not TLR2 ligation as early as 1 hour post stimulation and peaking at 6 hours. These results recapitulate the findings observed in previously published studies using isolated murine and human myeloid cells indicating that in vitro stimulated human whole blood can be used to interrogate the transcriptional kinetics response of innate cells to TLR ligands. Our study demonstrates that with a systems biology approach analysis of mRNA isolated from human whole blood can delineate both the temporal response and the key transcriptional differences following TLR2 and TLR4 ligation. 6 healthy human volunteers. 1ml whole blood stimulated in vitro with either LPS (1ng/ml), Pam3CSK4 (200ng/ml) or media for 0, 1, 3, 6 12 or 24 hours.
2014-07-11 | E-GEOD-55375 | biostudies-arrayexpress
Project description:Common missense mutations (D299G, T399I) have been recently identified in the human TLR4 gene. The aim of this study was to determine how TLR4 and associated mutants affect gene expression in Caco-2 cells. We used microarrays to asses gene expression profiles in Caco-2 stably overexpressing TLR4-WT, TLR4-D299G, TLR4-T399I or untransfected. Caco-2 clones stably overexpressing HA-tagged wildtype TLR4-WT, mutant TLR4-D299G or TLR4-T399I were generated. Prior to analysis, cell clones were cultured for 8 days in all experiments. RNA (triplicate) was extracted and hybridized on Affymetrix microarrays.
2011-10-10 | E-GEOD-26226 | 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. 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: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