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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| 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:Toll-like receptor 4 (TLR4), a pattern-recognition receptor located on the plasma membrane, senses extracellular danger signals to initiate inflammatory immune responses. It is initially synthesized in the endoplasmic reticulum (ER), undergoes N-linked glycosylation, and is subsequently transported to the Golgi before ultimately reaching the plasma membrane. However, the mechanisms underlying the processing and maturation of TLR4 in the ER remain elusive. Through whole genome-wide CRISPR screening, CCDC134 was identified as a critical and essential factor for TLR4-dependent inflammatory response. Localization of CCDC134 in the ER lumen rather than its exosome-mediated secretion is required for its role in TLR4 signaling. Loss of CCDC134 results in the retention of TLR4 in the ER for subsequent ER-associated degradation, and thus blockade of TLR4 maturation and plasma membrane trafficking. Defects in TLR4 processing and maturation in the ER in CCDC134-depleted cells are caused by aberrant hyperglycosylation and destabilization of glycoprotein 96 (gp96), a key chaperone of TLR4. These results suggest that CCDC134 controls gp96 glycosylation to facilitate TLR4 maturation in the ER.
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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
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Project description:This study focuses on the regulatory effect of ULK1 (Unc-51-like autophagy activating kinase 1) deficiency on TLR4 (Toll-like receptor 4) acetylation in THP-1 cells. ULK1, a key kinase involved in autophagy initiation, has been reported to participate in the regulation of various cellular processes, including inflammation and signal transduction. TLR4, a crucial pattern recognition receptor, plays a vital role in recognizing pathogen-associated molecular patterns and initiating innate immune responses, and its acetylation modification is closely related to the activation of downstream signaling pathways. In this study, ULK1-deficient THP-1 cells were constructed, and the acetylation level of TLR4 in the cells was detected by IP-MS methods. The results showed that the deficiency of ULK1 significantly promoted the acetylation of TLR4 in THP-1 cells, suggesting that ULK1 may act as a negative regulator of TLR4 acetylation.
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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: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: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:Staphylococcus aureus small colony variants (SCVs) are metabolically adapted, slow-growing subpopulations responsible for chronic, recurrent bovine mastitis through enhanced intracellular persistence and immune evasion. The role of Toll-like receptor 4 (TLR4) in regulating bovine mammary epithelial transcriptional responses to S. aureus SCV challenge remains poorly understood. Using CRISPR-Cas9-generated TLR4-knockout (TLR4-KO) MAC-T cells combined with RNA sequencing, global transcriptional responses of wild-type (WT) and TLR4-KO MAC-T cells infected with S. aureus SCV Heba3231 and its isogenic parental strain (PS) were compared. The WT cells mounted highly divergent S. aureus strain-specific responses, with only 0.5% overlap in differentially expressed genes between PS and SCV conditions. The PS infection induced apoptotic and HIF-1 signalling pathways, whereas SCV infection promoted lipid metabolic reprogramming, accompanied by suppression of epithelial barrier integrity genes. TLR4 disruption dramatically amplified transcriptional dysregulation, with a 192-fold increase for the PS (1,921 DEGs) and a 6.6-fold increase for SCV (2,279 DEGs) relative to WT infected controls. This revealed a large core set of TLR4-regulated genes with approximately 57% shared across S. aureus strains that govern innate immunity, structural homeostasis, and apoptotic coordination. WFDC2, ITGB3, SH3BGRL, and HKDC1 emerged as novel TLR4-dependent candidate genes. Collectively, these findings identify TLR4 as a key determinant of strain-specific transcriptional discrimination and epithelial homeostasis during S. aureus infection, with particular relevance to SCV-mediated persistence in bovine mastitis.
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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