Campylobacter jejuni enters gut epithelial cells and impairs intestinal barrier function through cleavage of occludin by serine protease HtrA

As the largest interface between the outside and internal milieu, the intestinal epithelium constitutes the first structural component facing potential luminal threats to homeostasis. This single-cell layer is the epicenter of a tightly regulated communication network between external and internal factors that converge to prime defensive responses aimed at limiting antigen penetration and the maintenance of intestinal barrier function. The defensive role developed by intestinal epithelial cells (IEC) relies largely on the variety of receptors they express at both extracellular (apical and basolateral) and intracellular compartments, and the capacity of IEC to communicate with immune and nervous systems. IEC recognize pathogen-associated molecules by innate receptors that promote the production of mucus, antimicrobial substances, and immune mediators. Epithelial cells are key to oral tolerance maintenance and also participate in adaptive immunity through the expression of immunoglobulin (Ig) receptors and by promoting local Ig class switch recombination. In IEC, different types of antigens can be sensed by multiple immune receptors that share signaling pathways to assure effective responses. Regulated defensive activity maintains intestinal homeostasis, whereas a breakdown in the control of epithelial immunity can increase the intestinal passage of luminal content and microbial invasion, leading to inflammation and tissue damage. In this review, we provide an updated overview of the type of immune receptors present in the human intestinal epithelium and the responses generated to promote effective barrier function and maintain mucosal homeostasis.

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Glutamine Protects Intestinal Barrier Function of Colon Epithelial Cells from Ethanol by Modulating Hsp70 Expression

Pharmacology ◽

10.1159/000345930 ◽

2013 ◽

Vol 91 (1-2) ◽

pp. 104-111 ◽

Cited By ~ 13

Author(s):

Reiko Akagi ◽

Michiko Ohno ◽

Kiminori Matsubara ◽

Mitsuaki Fujimoto ◽

Akira Nakai ◽

...

Keyword(s):

Epithelial Cells ◽

Barrier Function ◽

Intestinal Barrier ◽

Intestinal Barrier Function ◽

Hsp70 Expression

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A Soybean Resistant Protein-Containing Diet Increased the Production of Reg3γ Through the Regulation of the Gut Microbiota and Enhanced the Intestinal Barrier Function in Mice

Frontiers in Nutrition ◽

10.3389/fnut.2021.701466 ◽

2021 ◽

Vol 8 ◽

Author(s):

Tasuku Ogita ◽

Fu Namai ◽

Ayane Mikami ◽

Takahiro Ishiguro ◽

Koji Umezawa ◽

...

Keyword(s):

Epithelial Cells ◽

Barrier Function ◽

Functional Food ◽

Intestinal Barrier ◽

Intestinal Barrier Function ◽

Bacterial Invasion ◽

Direct Stimulation ◽

Intestinal Homeostasis ◽

Food Component ◽

Freeze Dried

The maintenance of intestinal homeostasis is necessary for a good quality of life, and strengthening of the intestinal barrier function is thus an important issue. Therefore, we focused on soybean resistant protein (SRP) derived from kori-tofu (freeze-dried tofu), which is a traditional Japanese food, as a functional food component. In this study, to investigate the effect of SRP on the intestinal barrier function and intestinal microbiota, we conducted an SRP free intake experiment in mice. Results showed that ingestion of SRP decreased the serum level of lipopolysaccharide-binding protein and induced the expression of Reg3γ, thereby improving the intestinal barrier function. In addition, SRP intake induced changes in the cecal microbiota, as observed by changes in β-diversity. In particular, in the microbiota, the up-regulation of functional gene pathways related to the bacterial invasion of epithelial cells (ko05100) was observed, suggesting that Reg3γ expression was induced by the direct stimulation of epithelial cells. The results of this study suggest that SRP is a functional food component that may contribute to the maintenance of intestinal homeostasis.

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The Sphingosine-1-Phosphate/Sphingosine-1-Phosphate Receptor 2 Axis in Intestinal Epithelial Cells Regulates Intestinal Barrier Function During Intestinal Epithelial Cells–CD4+T-Cell Interactions

Cellular Physiology and Biochemistry ◽

10.1159/000491985 ◽

2018 ◽

Vol 48 (3) ◽

pp. 1188-1200 ◽

Cited By ~ 8

Author(s):

Tanzhou Chen ◽

Ruoyang Lin ◽

Sisi Jin ◽

Renpin Chen ◽

Haibo Xue ◽

...

Keyword(s):

T Cell ◽

Epithelial Cells ◽

Barrier Function ◽

Intestinal Barrier ◽

Cd4 T Cell ◽

Intestinal Barrier Function ◽

T Cell Proliferation ◽

Intestinal Epithelial ◽

Mhc Ii ◽

Sphingosine 1 Phosphate

Background/Aims: Epithelial cells line the intestinal mucosa and form an important barrier for maintaining host health. This study aimed to explore the mechanism of the Sphingosine-1-phosphate (S1P)/Sphingosine-1-phosphate receptor 2 (S1PR2) pathway in intestinal epithelial cells (IECs) that participate in the intestinal barrier function. Methods: In this study, we constructed a knockout of the S1PR2 gene in mice, and Dextra sulfate sodium (DSS) was used to induce colitis. We isolated IECs from wild type (WT) and S1PR2–/– mice, and the endogenous expression of S1PR2 and Zonula occludens 1 (ZO-1) in IEC were detected by Western blot. Next, the major histocompatibility complex II (MHC-II) expression was analyzed by reverse transcription quantitative real-time (RT-qPCR) and flow cytometry. The in vivo and in vitro intestinal permeability were evaluated by serum fluorescein isothiocyanate (FITC) concentration. The tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interferon-γ (IFN-γ) levels in cell suspension were analyzed by enzyme-linked immuno sorbent assay (ELISA). A carboxyfluorescein diacetate succinimidyl ester (CFSE) assay was used to detect the T-cell proliferation in a co-culture system. Results: The intestinal mucosal barrier damage in S1PR2–/– mice was more severe than in the WT mice, and there were more CD4+T-cells in the colon tissue of DSS-treated S1PR2–/– mice. Either the mouse colon carcinoma cell line (CT26. WT) or the IECs upregulated MHC-II expression, which then promoted CD4+T-cell proliferation. The S1P/S1PR2 pathway controlled MHC-II expression to regulate CD4+T-cell proliferation via the extracellular signal-regulated kinase (ERK) pathway. In addition, the IFN-γ that was secreted by CD4+T-cells increased DSS-induced damage of intestinal epithelial cell barrier function. ZO-1 expression was increased by S1P in CT26.WT cells, while S1PR2 antagonist JTE-013 expression was downregulated. However, in CT26.WTsi-S1PR2 cells, S1P had no effect on ZO-1 expression. Conclusions: The S1P/S1PR2 axis in IECs mediated CD4+T-cell activation via the ERK pathway and MHC-II expression to regulate intestinal barrier function.

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Colitis Linked to Endoplasmic Reticulum Stress Induces Trypsin Activity Affecting Epithelial Functions

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjab035 ◽

2021 ◽

Author(s):

Núria Solà Tapias ◽

Alexandre Denadai-Souza ◽

Claire Rolland-Fourcade ◽

Muriel Quaranta-Nicaise ◽

Catherine Blanpied ◽

...

Keyword(s):

Er Stress ◽

Serine Protease ◽

Barrier Function ◽

Protease Activity ◽

Intestinal Epithelial Cells ◽

Intestinal Barrier ◽

Intestinal Barrier Function ◽

Intestinal Epithelial ◽

Trypsin Activity ◽

Serine Protease Activity

Abstract Background and Aims Intestinal epithelial cells [IECs] from inflammatory bowel disease [IBD] patients exhibit an excessive induction of endoplasmic reticulum stress [ER stress] linked to altered intestinal barrier function and inflammation. Colonic tissues and the luminal content of IBD patients are also characterized by increased serine protease activity. The possible link between ER stress and serine protease activity in colitis-associated epithelial dysfunctions is unknown. We aimed to study the association between ER stress and serine protease activity in enterocytes and its impact on intestinal functions Methods The impact of ER stress induced by Thapsigargin on serine protease secretion was studied using either human intestinal cell lines or organoids. Moreover, treating human intestinal cells with protease-activated receptor antagonists allowed us to investigate ER stress-resulting molecular mechanisms that induce proteolytic activity and alter intestinal epithelial cell biology. Results Colonic biopsies from IBD patients exhibited increased epithelial trypsin-like activity associated with elevated ER stress. Induction of ER stress in human intestinal epithelial cells displayed enhanced apical trypsin-like activity. ER stress-induced increased trypsin activity destabilized intestinal barrier function by increasing permeability and by controlling inflammatory mediators such as C-X-C chemokine ligand 8 [CXCL8]. The deleterious impact of ER stress-associated trypsin activity was specifically dependent on the activation of protease-activated receptors 2 and 4. Conclusions Excessive ER stress in IECs caused an increased release of trypsin activity that, in turn, altered intestinal barrier function, promoting the development of inflammatory process.

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Sa1194 - Cdca Impaired Intestinal Barrier Function and Increased Proinflammatory Cytokine Release from Small Intestinal Epithelial Cells

Gastroenterology ◽

10.1016/s0016-5085(18)31275-7 ◽

2018 ◽

Vol 154 (6) ◽

pp. S-273

Author(s):

Tomoki Horikawa ◽

Tadayuki Oshima ◽

Min Li ◽

Yoshitaka Kitayama ◽

Hirotsugu Eda ◽

...

Keyword(s):

Epithelial Cells ◽

Barrier Function ◽

Proinflammatory Cytokine ◽

Intestinal Epithelial Cells ◽

Intestinal Barrier ◽

Intestinal Barrier Function ◽

Intestinal Epithelial ◽

Cytokine Release ◽

Small Intestinal

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PG-mediated closure of paracellular pathway and not restitution is the primary determinant of barrier recovery in acutely injured porcine ileum

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00532.2002 ◽

2003 ◽

Vol 285 (5) ◽

pp. G967-G979 ◽

Cited By ~ 39

Author(s):

Jody L. Gookin ◽

Joseph A. Galanko ◽

Anthony T. Blikslager ◽

Robert A. Argenzio

Keyword(s):

Epithelial Cells ◽

Barrier Function ◽

Intestinal Barrier ◽

Acute Injury ◽

Intestinal Barrier Function ◽

Ileal Mucosa ◽

Epithelial Barrier Function ◽

Ussing Chambers ◽

Relative Contribution ◽

Primary Determinant

Small bowel epithelium is at the frontline of intestinal barrier function. Restitution is considered to be the major determinant of epithelial repair, because function recovers in parallel with restitution after acute injury. As such, studies of intact mucosa have largely been replaced by migration assays of cultured epithelia. These latter studies fail to account for the simultaneous roles played by villous contraction and paracellular permeability in recovery of barrier function. NSAIDs result in increased intestinal permeability and disease exacerbation in patients with inflammatory bowel disease (IBD). Thus we examined the reparative attributes of endogenous PGs after injury of ileal mucosa by deoxycholate (6 mM) in Ussing chambers. Recovery of transepithelial electrical resistance (TER) from 20-40 Ω·cm2 was abolished by indomethacin (Indo), whereas restitution of 40-100% of the villous surface was unaffected despite concurrent arrest of villous contraction. In the presence of PG, resident crypt and migrating epithelial cells were tightly apposed. In tissues treated with Indo, crypt epithelial cells had dilated intercellular spaces that were accentuated in the migrating epithelium. TER was fully rescued from the effects of Indo by osmotic-driven collapse of the paracellular space, and PG-mediated recovery was significantly impaired by blockade of Cl- secretion. These studies are the first to clearly distinguish the relative contribution of paracellular resistance vs. restitution to acute recovery of epithelial barrier function. Restitution was ineffective in the absence of PG-mediated paracellular space closure. Failure of PG-mediated repair mechanisms may underlie barrier failure resulting from NSAID use in patients with underlying enteropathy.

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