Mucosal epithelial barrier repair to maintain pig health
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Keywords:
Paracellular transport
Barrier function
Claudin
Intestinal epithelium
Intestinal mucosa
Abstract Dysfunction of the epithelial barrier is a hallmark of inflammatory intestinal diseases. The intestinal epithelial barrier is maintained by expression of tight junctions that connect adjacent epithelial cells and seal the paracellular space. IL-22 is critical for the maintenance of intestinal barrier function through promoting antipathogen responses and regeneration of epithelial tissues in the gut. However, little is known about the effects of IL-22 on the regulation of tight junctions in the intestinal epithelium. In this study we report that IL-22 signals exclusively through the basolateral side of polarized Caco-2 cell monolayers. IL-22 treatment does not affect the flux of uncharged macromolecules across cell monolayers but significantly reduces transepithelial electrical resistance (TEER), indicating an increase of paracellular permeability for ions. IL-22 treatment on Caco-2 monolayers and on primary human intestinal epithelium markedly induces the expression of Claudin-2, a cation–channel-forming tight junction protein. Furthermore, treatment of IL-22 in mice upregulates Claudin-2 protein in colonic epithelial cells. Knocking down Claudin-2 expression with small interfering RNA reverses the reduction of TEER in IL-22–treated cells. Moreover, IL-22–mediated upregulation of Claudin-2 and loss of TEER can be suppressed with the treatment of JAK inhibitors. In summary, our results reveal that IL-22 increases intestinal epithelial permeability by upregulating Claudin-2 expression through the JAK/STAT pathway. These results provide novel mechanistic insights into the role of IL-22 in the regulation and maintenance of the intestinal epithelial barrier.
Paracellular transport
Claudin
Barrier function
Intestinal epithelium
Caco-2
Intestinal mucosa
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The aim of the study was to investigate the barrier function of Peyer’s patches epithelium, which covers the clusters of organized lymphoid tissues in the small intestinal. We used the Ussing chamber method to determine electrophysiological characteristics of epithelium and Western blot method and immunohistochemistry to investigate expression of tight junction proteins. We revealed that Peyer’s patches epithelium, which is specialized in sampling and transporting of antigen structures, has lower conductance compare to adjacent intestinal villous epithelium, the main function of which is to uptake ions, water and nutrients. On molecular level Peyer’s patch epithelium has lower expression of claudin-2 and claudin-7, which increases the permeability of the intercellular space, and higher expression of claudin-5 and -8, which decreases the paracellular pathway. Immunohistochemistry confirmed localization of claudins in the tight junction complex. We suggest that the restriction of paracellular transport is a prerequisite for the antigen presentation through specialized M-cells in Peyer’s patches epithelium. Refs 29. Figs 4.
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Intestinal mucosa
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Paracellular transport
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Intestinal epithelium
Intestinal mucosa
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The pig represents a preferred model for the analysis of intestinal immunology. However, the barrier of the follicle-associated epithelium (FAE) covering porcine Peyer's patches (PP) has not yet been characterized in detail. This study aimed to perform this characterization in order to pave the way toward an understanding of the functional contribution of epithelial barrier properties in gut immunology. Porcine tissue specimens were taken from the distal small intestine in order to obtain electrophysiological data of PP FAE and neighboring villous epithelium (VE), employing the Ussing chamber technique. Transepithelial resistance (TER) and paracellular fluorescein flux were measured, and tissues were morphometrically compared. In selfsame tissues, expression and localization of major tight junction (TJ) proteins (claudin-1, -2, -3, -4, -5, and -8) were analyzed. PP FAE specimens showed a higher TER and a lower apparent permeability for sodium fluorescein than VE. Immunoblotting revealed an expression of all claudins within both epithelia, with markedly stronger expression of the sealing TJ protein claudin-4 in PP FAE compared with the neighboring VE. Immunohistochemistry confirmed the expression and localization of all claudins in both PP FAE and VE, with stronger claudin-4 abundance in PP FAE. The results are in accordance with the physiological function of the FAE, which strongly regulates and limits antigen uptake determining a mandatory transcellular route for antigen presentation, highlighting the importance of this structure for the first steps of the intestinal immune response. Thus, this study provides detailed insights into the specific barrier properties of the porcine FAE covering intestinal PP, at the interface of intestinal immunology and barriology.
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Tight junctions (TJs) are widely expressed in the most apical portion of both epithelial and endothelial cell-cell interactions, serving as a structural and functional basis for material transport through the paracellular pathway. TJs are multi-protein complex composed of transmembrane and cytoplasmic proteins. TJs constitute pores allowing materials with specific size and electrical charge to pass through the paracellular pathway, which is so called "barrier" function. Besides, TJs also separate the lumen and interstitial space of epithelium and endothelium by the function of "fence". Recently, there is increasing body of evidence regarding the crucial role of TJs, together with the possible signaling pathways, in many epithelial cells, such as salivary, airway, intestinal and renal epithelial cells. The present review focuses on the latest research progresses on TJs, including TJ's composing, structure, and function measurement, as well as the mechanisms for modulating TJ's functions in some important epithelial cell types. We hope that the review may provide new insight into the therapeutic strategy of epithelium-related disease by targeting TJs.
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Abstract: Epithelial barrier function is determined by trans‐ and paracellular permeabilities, the latter of which is mainly influenced by tight junctions (TJs) and apoptotic leaks within the epithelium. The present article aims to present experimental evidence for a functional role of epithelial apoptoses by means of cell culture models as well as in tissues from patients with inflammatory bowel disease. It is shown that epithelial apoptoses are sites of elevated conductance within the intestinal epithelium and that proinflammatory cytokines like TNF‐α upregulate both the apoptotic rate and single apoptotic conductivity, making cytokine‐induced apoptosis functionally far more relevant than is spontaneous apoptosis. In ulcerative colitis and Crohn's disease (CD), but not in collagenous colitis, apoptotic rates are increased to about 5%, in mild‐to‐moderately inflamed colon specimens, where as the control apoptotic rate is about 2%. Thus, epithelial apoptoses lead to a loss of ions and water into the intestinal lumen, causing leak flux diarrhea and enabling small antigens of <4,000 Da in the intestinal lumen to enter the intestinal mucosa, thereby perpetuating inflammatory responses. In addition to TNF‐α, interleukin (IL)‐13 is an important inductor of epithelial apoptosis in Th2 immune responses. Therapeutically,TNF‐α‐antibodies (infliximab) can restore barrier function in Crohn's disease by downregulating epithelial apoptoses, while epithelial TJs are unaffected.
Barrier function
Proinflammatory cytokine
Intestinal epithelium
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Intestinal mucosa
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Intestinal epithelium functions as a tissue barrier to prevent interaction between the internal compartment and the external milieu. Intestinal barrier function also determines epithelial polarity for the absorption of nutrients and the secretion of waste products. These vital functions require strong integrity of tight junction proteins. In fact, intestinal tight junctions that seal the paracellular space can restrict mucosal-to-serosal transport of hostile luminal contents. Tight junctions can form both an absolute barrier and a paracellular ion channel. Although defective tight junctions potentially lead to compromised intestinal barrier and the development and progression of gastrointestinal (GI) diseases, no FDA-approved therapies that recover the epithelial tight junction barrier are currently available in clinical practice. Here, we discuss the impacts and regulatory mechanisms of tight junction disruption in the gut and related diseases. We also provide an overview of potential therapeutic targets to restore the epithelial tight junction barrier in the GI tract.
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Septate junctions
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Claudin
Occludin
Intestinal epithelium
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Intestinal mucosa
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The small intestinal permeability barrier is dependent on tight junction (TJ) complexes that separate the external lumen from the underlying mucosa. Apical TJs consist of integral transmembrane proteins including occludin, claudins and ZO-1 as well as the cytoplasmic plaque of TJ-associated adaptor, scaffolding and signalling proteins. Although the function of occludin at the TJ remains unclear, the dynamic mobility of occludin, claudins and ZO-1 to and from the TJ suggests occludin may play a key role in regulation of TJ structure and function, regulated by occludin phosphorylation status. Defects in TJ barrier function have been implicated in a range of inflammatory diseases such as inflammatory bowel disease (IBD) and pathogens such as Toxoplasma gondii target this complex as a route of infection. As oral infection is the primary cause of toxoplasmosis, the first point of contact between T. gondii and the host is the small intestinal epithelium and studies by Weight, 2012 show occludin may be involved in T. gondii paracellular transmigration of the small intestinal epithelium.
The aim of this research was to investigate T. gondii paracellular transmigration using an in vitro model of the small intestinal epithelium and elucidate the role of occludin both in regulation of the TJ barrier and as a receptor for T. gondii infection. The results presented in this thesis demonstrate that T. gondii infects the small intestinal epithelium via the paracellular pathway and occludin was shown to play a key role both in regulation of the TJ paracellular barrier and as a receptor for T. gondii infection by parasite-mediated modulation of the occludin C-terminus phosphorylation status and direct binding to occludin ECL1; suggesting T. gondii interactions with occludin are a potential mechanism of paracellular transmigration of the small intestinal epithelium.
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Claudin
Paracellular transport
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Intestinal epithelium
Transcytosis
Intestinal mucosa
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The intestinal epithelium forms a highly dynamic and selective barrier that controls absorption of fluid and solutes while restricting pathogen access to underlying tissues. Barrier properties are achieved by intercellular junctions that include an apical tight junction (TJ) and subjacent adherens junctions and desmosomes. The TJ tetraspan claudin proteins form pores between epithelial cells to control paracellular fluid and ion movement. In addition to regulation of barrier function, claudin family members control epithelial homeostasis and are expressed in a spatiotemporal manner in the intestinal crypt–luminal axis. This delicate balance of physiologic differential claudin protein expression is altered during mucosal inflammation. Inflammatory mediators influence transcriptional regulation, as well as endocytic trafficking, targeting, and retention of claudins in the TJ. Increased expression of intestinal epithelial claudin‐1, ‐2, and ‐18 with downregulation of claudin‐3, ‐4, ‐5, ‐7, ‐8, and ‐12 has been observed in intestinal inflammatory disorders. Such changes in claudin proteins modify the epithelial barrier function in addition to influencing epithelial and mucosal homeostasis. An improved understanding of the regulatory mechanisms that control epithelial claudin proteins will provide strategies to strengthen the epithelial barrier function and restore mucosal homeostasis in inflammatory disorders.
Claudin
Paracellular transport
Barrier function
Adherens junction
Homeostasis
Intestinal mucosa
Intestinal epithelium
Transcellular
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