Toll-like Receptor 2 Signalling and the Lysosomal Machinery in Barrett’s Esophagus

Verbeek, Romy E.; Siersema, Peter D.; Vleggaar, Frank P.; Kate, Fiebo J. ten; Posthuma, George; Souza, Rhonda F.; Haan, Judith de; Baal, Jantine W. P. M. van

doi:10.15403/jgld.2014.1121.253.rc2

Cited by 14 publications

(16 citation statements)

References 39 publications

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“…Both primary esophageal epithelial cells and the EPC2‐hTERT cell line express TLR1 through TLR6 , with minimal expression of TLR7 through TLR10, CD14, and CLEC7A. As in prior studies, we observe robust mRNA expression of TLR2 and TLR3 . We did not observe significant differences in PRR expression between cell lines from EoE patients and controls (Figure A).…”

Section: Resultssupporting

confidence: 80%

Toll‐like receptor 2 stimulation augments esophageal barrier integrity

Ruffner

Song

Maurer

et al. 2019

Allergy

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Background: Germline-encoded innate immune pattern recognition receptors (PRR) are expressed at epithelial surfaces and modulate epithelial defenses. Evidence suggests that stimulation of the Toll-like receptor (TLR) family of PRR may regulate epithelial barrier integrity by upregulating tight junction (TJ) complex protein expression, but it is not known whether this mechanism is utilized in esophageal epithelial cells.TJ complex proteins maintain intact barrier function and are dysregulated in atopic disorders including eosinophilic esophagitis. Methods: Pattern recognition receptors expression was assessed in EoE and controlprimary esophageal epithelial cells, demonstrating robust expression of TLR2 and TLR3. The three-dimensional air-liquid interface culture (ALI) model was used to test whether TLR2 or TLR3 stimulation alters epithelial barrier function using an in vitro model of human epithelium. Transepithelial electrical resistance (TEER) and FITC-Dextran permeability were evaluated to assess membrane permeability. ALI cultures were evaluated by histology, immunohistochemistry, Western blotting, and chromatin immunoprecipitation (ChIP).Results: TLR3 stimulation did not change TEER in the ALI model. TLR2 stimulation increased TEER (1.28-to 1.31-fold) and decreased paracellular permeability to FITC-Dextran, and this effect was abolished by treatment with anti-TLR2 blocking antibody. TJ complex proteins claudin-1 and zonula occludens-1 were upregulated following TLR2 stimulation, and ChIP assay demonstrated altered histone 4 acetyl binding at the TJP1 enhancer and CLDN1 enhancer and promoter following zymosan treatment, implying the occurrence of durable chromatin changes. Conclusions:Our findings implicate the TLR2 pathway as a potential regulator of esophageal epithelial barrier function and suggest that downstream chromatin modifications are associated with this effect. K E Y W O R D Seosinophilic esophagitis, epithelium, innate immunity, tight junctions, toll-like receptors

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Section: Resultssupporting

confidence: 80%

Toll‐like receptor 2 stimulation augments esophageal barrier integrity

Ruffner

Song

Maurer

et al. 2019

Allergy

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“…Our study showed predominantly superficial increase in TLR2 expression in reflux oesophagitis. The increase in TLR2 expression was consistent with the general pattern reported for TLR2 in inflammatory conditions [23,24] and also with a study from Verbeek et al [25], who showed that TLR2 mRNA expression increased non-significantly in reflux oesophagitis. The shift to more superficial distribution of TLR2 suggests that luminal TLR2 ligands might play a role in GERD pathogenesis.…”

Section: Discussionsupporting

confidence: 91%

Pathophysiology of reflux oesophagitis: role of Toll-like receptors 2 and 4 and Farnesoid X receptor

et al. 2021

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The pathogenesis of gastroesophageal reflux disease (GERD) is not fully understood. It involves the activation of mucosal immune-mediated and inflammatory responses. Toll-like receptors (TLR) 2 and TLR4 are pattern-recognition receptors of the innate immune system; they recognize microbial and endogenous ligands. Farnesoid X receptor (FXR) is a bile acid receptor that regulates the inflammatory response. We aimed to evaluate TLR2, TLR4 and FXR expression patterns in GERD. We re-evaluated 84 oesophageal biopsy samples according to the global severity (GS) score, including 26 cases with histologically normal oesophagus, 28 with histologically mild oesophagitis and 30 with severe oesophagitis. We used immunohistochemistry and in situ hybridization to assess the expression patterns of TLR2, TLR4 and FXR in oesophageal squamous cells. Immunohistochemistry showed that nuclear and cytoplasmic TLR2 was expressed predominantly in the basal layer of normal oesophageal epithelium. In oesophagitis, TLR2 expression increased throughout the epithelium, and the superficial expression was significantly more intensive compared to normal epithelium, p <0.01. Nuclear and cytoplasmic TLR4 was expressed throughout the thickness of squamous epithelium, with no change in oesophagitis. FXR was expressed in the nuclei of squamous cells, and the intensity of the expression increased significantly in oesophagitis (p <0.05). FXR expression correlated with basal TLR2. In situ hybridization confirmed the immunohistochemical expression patterns of TLR2 and TLR4. In GERD, TLR2, but not TLR4, expression was upregulated which indicates that innate immunity is activated according to a specific pattern in GERD. FXR expression was increased in GERD and might have a regulatory connection to TLR2.

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“…First, alteration of the microbiota may result in inflammation, and persistent chronic inflammation may promote carcinogenesis[71]. The disequilibrium between human immunity and microbiota may change the compositions of essential bacterial molecules at certain organs or sites and then form microorganism-associated molecular patterns (MAMPs)[71], such as toll-like receptors (TLRs) and nucleotide-binding-oligomerization-domain (NOD)-like receptors[72,73]. Then, the subsequent activation of related pathways may lead to the production and release of some target genes involved in inflammation[73], such as cytokines, chemokines and other inflammatory factors.…”

Section: Mechanismsmentioning

confidence: 99%

Alteration of the esophageal microbiota in Barrett's esophagus and esophageal adenocarcinoma

Guo

Liu

et al. 2019

WJG

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The incidence of esophageal adenocarcinoma (EAC) has increased in recent decades, and its 5-year survival rate is less than 20%. As a well-established precursor, patients with Barrett's esophagus (BE) have a persistent risk of progression to EAC. Many researchers have already identified some factors that may contribute to the development of BE and EAC, and the identified risks include gastroesophageal reflux (GER), male sex, older age, central obesity, tobacco smoking, Helicobacter pylori ( H. pylori ) eradication, and the administration of proton pump inhibitors (PPIs) and antibiotics. The human gut harbors trillions of microorganisms, the majority of which are bacteria. These microorganisms benefit the human host in many ways, such as helping in digestion, assisting in the synthesis of certain vitamins, promoting the development of the gastrointestinal immune system, regulating metabolism and preventing invasion by specific pathogens. In contrast, microbial dysbiosis may play important roles in various diseases, such as inflammation and cancers. The composition of the microbiota located in the normal esophagus is relatively conserved without distinct microbial preferences in the upper, middle and lower esophagus. Six major phyla constitute the esophageal microbiota, including Firmicutes , Bacteroides , Actinobacteria , Proteobacteria , Fusobacteria and TM7 , similar to the oral microbiota. Streptococcus dominates the esophageal microbiota. However, the microbiota varies in different esophageal diseases compared to that in the healthy esophagus. The type I microbiota, which is primarily composed of gram-positive bacteria, is closely associated with the normal esophagus, while type II microbiota has enriched gram-negative bacteria and is mainly associated with the abnormal esophagus. These increased gram-negative anaerobes/microaerophiles include Veillonella , Prevotella , Haemophilus , Neisseria , Granulicatella and Fusobacterium , many of which are associated with BE. The microbial diversity in the esophagus is decreased in EAC patients, and Lactobacillus fermentum is enriched compared to that in controls and BE patients. Furthermore, the microbiota may be associated with BE and EAC by interacting with their risk factors, including central obesity, GER, H. pylori , administration of PPIs and antibiotics. Therefore, a large gap in research must be bridged to elucidate the associations among these factors. Some studies have already proposed several potential mechanisms by which the microbiota participates in human carcinogenesis by complicated interactions with the human host immune system and signaling pathways. The activa...

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Toll-like Receptor 2 Signalling and the Lysosomal Machinery in Barrett’s Esophagus

Cited by 14 publications

References 39 publications

Toll‐like receptor 2 stimulation augments esophageal barrier integrity

Toll‐like receptor 2 stimulation augments esophageal barrier integrity

Pathophysiology of reflux oesophagitis: role of Toll-like receptors 2 and 4 and Farnesoid X receptor

Alteration of the esophageal microbiota in Barrett's esophagus and esophageal adenocarcinoma

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