Under physiological conditions, brain microvascular endothelial cells form a barrier limiting the extravasation of cells of the immune system like monocytes, lymphocytes and other leukocytes. It has been shown in this context that leukocytes can transmigrate to the BBB without net changes in vascular permeability and cell—cell contacts Cramer MS is characterised as a chronic and progressive CNS disease with a remitting-relapsing profile. In the course of the disease, both demyelination and microvascular inflammation have been described as central pathophysiological insults.
Cytokine-promoted opening of the BBB has been shown to occur due to degradation and decreased synthesis of TJ proteins Chang and Werb ; Harkness et al. Particularly, the TJ proteins occludin and ZO-1 have been shown to be negatively affected by the presence of these pro-inflammatory cytokines. Searching for the mechanism of TJ protein degradation, consecutive studies showed, that in many neuroinflammatory conditions, including MS, the matrix metalloproteinases MMP play an important role in disrupting the BBB.
Tissue inhibitors of metalloproteinases TIMPs form complexes with either activated MMPs or with their pro-forms after their secretion, thus regulating MMP activity under physiological conditions Brew et al. MMPmediated opening of the BBB then allows amplification of the inflammation, as demonstrated by radioisotopes Kermode et al.
This study further demonstrated that the administration of the glucocorticoids dexamethasone and hydrocortisone preserved the functional integrity of the TJs and adherens junctions under pro-inflammatory conditions, chiefly by maintaining the levels of the TJ components occludin, claudin-1, claudin, ZO-1 and VE-cadherin, while dexamethasone effects on claudin-5 were negligible Blecharz et al.
Since it was shown that the main protein buiding up the barrier appears to be occludin, while claudin-5 protein, which is also well detectable in non-BBB endothelial cells, does not seem to influence barrier properties to the same extent Foerster et al. One may speculate that the lower overall occludin contents of endothelial cells of the cerebellar BBB compared to the cerebral BBB can partly explain the greater sensitivity of the cerebellar BBB to inflammatory stimuli.
The cochlea of the inner ear is divided into two compartments of different ionic composition. Besides, hereditary defects in the gap junction proteins connexin and connexin Sabag et al. The importance of claudin expression in the cochlea was demonstrated by the identification of two different CLDN14 mutations that cause nonsyndromic recessive deafness DFNB29 in two large consanguineous Pakistani families Wilcox et al. By in situ hybridization and immunofluorescence labeling mouse claudin expression in the sensory epithelium of the organ of Corti was observed.
By the generation and characterisation of claudin knockout mice as a model for autosomal-recessive deafness DFNB29 it was revealed that deafness occurred due to death of outer hair cells. Searching for the factors that promoted increased death of outer hair cells, morphology of the TJs of claudin knockout mice was evaluated. It was demonstrated that TJ strands between supporting cells and between outer hair cells and supporting cells in the organ of Corti are still present and appear morphologically normal in freeze fracture replicas.
The analysed TJ strands which are composed of multiple claudins were thus concluded to have rather a functional than an ultrastructural defect Ben-Yosef et al. By the identification of two claudin missense mutations that were unable to form TJs after ectopic expression of CLDN14 in L mouse fibroblastes, Wattenhofer et al. Inherited and acquired defects in epithelial membrane transport are responsible for many human diseases.
Tight Junctions and the Intestinal Barrier
In the kidney, tubular claudins play a role in extracellular or paracellular permeability. The structural backbone of the paracellular pathway must provide for the significant substrate selectivity and functional heterogeneity between nephron segments and thus also plays a pathophysiologic role in renal diseases.
Recent studies Simon et al. As a member of the claudin family of TJ proteins claudin exhibits four transmembrane spans with two extracellular loops and both termini located in the cytoplasm. It is therefore likely that PCLN-1 selectively mediates the barrier to divalent but not monovalent cations.
Thus, not only can the paracellular barrier discriminate between charged and uncharged solutes, but it may also exhibit an even higher level of specificity distinguishing charge and ionic radius and size of the hydrate shell. As to molecular investigations based on the use of diverse cell culture models for kidney epithelial cells, there is some discrepancy between results obtained upon overexpression of PLCN-1 in two different kidney epithelial cell lines used. Another recent study performed in the porcine proximal tubule LLC-PK1 cells suggests that paracellin-1 functions to modulate paracellular conductance and not transcellular transport.
The mutation TR for example prevents interaction of claudin with ZO-1 and results in lysosomal targeting of claudin instead. Protein kinase A PKA mediates phosphorylation of claudin at Ser, failure of which equally leads to dissociation of claudin from ZO-1 and its translocation into the lysosomes Ikari et al.
Recently, Konrad et al.
They showed that the renal phenotype of the affected patients was virtually undistinguishable from that of patients who presented with FHHNC with proven CLDN16 mutations. However, the affected individuals in these families also have severe visual impairment, characterized by macular colobomata, significant myopia, and horizontal nystagmus Konrad et al. Konrad et al. CLDN19, which encodes the tight-junction protein claudin was demonstrated to be highy expressed in renal tubules and the retina. In an effort to understand the mechanisms underlying the roles of the two claudins in mediating paracellular ion reabsorption in the kidney, Goodenough and co workers Hou et al.
The barrier between the vascular lumen and neural layers in the retina and the brain parenchyme maintains a characteristic microenvironment and is essential for proper neuronal function. This blood-retinal barrier BRB consists of two anatomical entities: an inner BRB formed by junctions between endothelial cells of the retinal capillaries, and an outer BRB composed of TJs between retinal pigment epithelial cells.
Clinical evidence from fluorescein angiography has demonstrated that the inner BRB appears to be the primary site of vascular leakage leading to macular edema. The principal proteins found in the retinal endothelial TJs are occludin and claudin-5 Dejana et al.
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Loss of the BRB integrity and vascular permeability leading to macular edema Vitale et al. Macular edema in turn is thought to be directly responsible for vision loss in diabetic retinopathy Felinski and Antonetti Levels of VEGF, originally identified as an angiongenic factor serving as a mitogen for vascular endothelial cells have been recently correlated with increased vascular permeability Felinski and Antonetti , compatible with increased VEGF levels detected in the vitreous of diabetic patients for decades. There is enough evidence to show that diabetes and VEGF induce retinal vascular permeability by altering TJ complexes, evidenced for instance by the decrease in occludin content in the retinas of diabetic rats Felinski and Antonetti In cultured primary bovine retinal endothelial cells, this observation was mirrored by the observation of decreased occludin contents after VEGF administration Antonetti et al.
Follow-up investigation underlined this and showed down-regulation of occludin in retinal endothelial cells in culture after VEGF stimulation. Phosphorylation of occludin and ZO-1 likely contribute to dysregulated endothelial paracellular permeability Abbott et al.distetuno.tk
JAM-C Regulates Tight Junctions and Integrin-mediated Cell Adhesion and Migration
Regulation of PKC activity and TJ protein modifications may thus have therapeutic implications for treatment of diabetic retinopathy. Recent investigation has further revealed that alterations of the BRB may involve the active proteolytic breakdown of the endothelial cell TJs by MMPs as also evidenced in the case of MS compare above Leppert et al.
Specifically, elevated levels of MMP-9 have been seen when retinal endothelial cells were exposed to high glucose conditions as a cell culture model of diabetes, leading to proteloytic degradation of specifically the TJ protein occludin followed by disruption of the overall TJ complex Giebel et al. Changes in TJ function have been shown to be an early and key aspect in cancer metastasis Ehler et al. Interestingly, there is an absence or significant loss of claudin-1 expression in several established breast cancer cell lines. Claudin-1 expression in primary human mammary epithelial cells, in contrast to low or undetectable levels of expression in a number of breast tumors and breast cancer cell lines, points to claudin-1 as a possible tumor-suppressor gene.
In sections from surgically resected breast specimens, a significant loss of claudin-1 protein in breast cancer cells could be shown by immunohistochemistry Tokes et al. This finding suggests that claudin-1 may play a role in invasion and metastasis. The expression profile of claudin-1 in non-malignant versus tumor-derived cells has made this gene an interesting candidate for involvement in tumorigenesis, namely by acting as a suppressor of mammary epithelial proliferation.
However, neither in sporadic or hereditary breast cancers, nor in breast cancer cell lines they found evidence for a role of aberrant claudin-1 in breast tumorigenesis and concluded that other regulatory or epigenetic factors could be involved in the down-regulation of the CLDN1 gene during breast cancer development. A correlation between TJ abnormalities and neoplasia can be supported by several observations: alterations in the number, appearance, and permeability of TJs have been demonstrated in various cancer types Cochand-Priollet et al.
At the molecular level, the Drosophila lethal 1 discs-large-1 gene dlg product, which localises to TJ-related insect septate junctions has been shown to regulate epithelial cell proliferation. Genetic loss of dlg leads to a neoplastic overgrowth phenotype Woods and Bryant The loss of expression of claudin-1 itself has been demonstrated in several mammary carcinoma cell lines Swisshelm et al. The expression of the TJ plaque protein ZO-1 has been shown to be reduced in breast carcinomas or breast cancer cells Hoover et al.
These findings support the hypothesis that claudin-1 might be involved in the development of breast cancer and possibly in other epithelial tumors too. The molecular pathways leading toward the loss of claudin-1 expression however, remain to be explained. The enterotoxin protein has been elucidated to intrude the cells by interacting with epithelial TJ, including certain claudins. Toxin-induced cytolytic pore-formation is a prerequisite for this and involves residues in the N-terminal half of CPE protein, while residues near the C-terminus are required for binding to claudins.
CPE was then perceived to affect TJ structure and function in a way that permeability properties of the epithelial layer are altered leading to diarrhea McClane Further investigation has determined the isoforms of claudins targeted by CPE. Sonoda et al. They were further able to show that in the presence of C-CPE, reconstituted TJ strands gradually disintegrated and disappeared from their cell surface in C3L cells.
As a consequence, because diverse claudins are overexpressed on some human cancers, the toxin became interesting for targeting chemotherapy in the manner of a Trojan horse Long et al. Recently, van Itallie et al. The structure was shown to be a nine-strand beta sandwich with previously unappreciated similarity to the receptor-binding domains of several other toxins of spore-forming bacteria, giving strong evidence for the presence of a common ancestor for several receptor-binding domains of bacterial toxins Van Itallie et al. They further were able to clarify that the sequence crystallized binds to purified human claudin-4 with a stoichiometry.
The binding affinity was determined to be in the submicromolar range similar to that observed for binding of native toxin to cells Van Itallie et al. These results could now provide a structural framework to advance therapeutic applications of the toxin. The discovery of the existence of occludin- and claudin-based TJs constituting a permeability barrier in epithelial and endothelial cells has paved the way for the elucidation of the molecular background of diverse human diseases the pathogenesis of which had been unclear before. It became clear that the presence of TJs is indispensable for tissue compartmentalisation and cellular homeostasis.
Disturbances in TJ function are reflected in many diseases, but on the other hand, awareness of their involvement has facilitated therapy enormously. For instance, antiinflammatory or antimetastatic drugs could be developed based on their ability to repair broken barrier function. These strategies have become indispensable in the treatment of disease like MS, inflammatory bowel disease or diabetic retinopathy. Following the strategy of pathogenic agents, which use TJ proteins as a docking station to invade cells, even strategies for drug delivery techniques could be implemented.
Future attempts will have to address the role of occludin and the exact contribution of the diverse claudins to the formation of ion selective pores, which are still open questions. A more thorough understanding will greatly facilitate diagnosis and the development of specific treatment regimens for diseases originating from impaired TJ function. The author is especially thankful toDetlev Drenckhahn for constructive suggestions and critical reading of the manuscript. The author is grateful to Kinga Blecharz for editing expertise and Malgorzata Burek for efficient and pleasant help in collection of material.
Skip to main content Skip to sections. Advertisement Hide. Download PDF. Tight junctions and the modulation of barrier function in disease. Open Access. First Online: 16 April Introduction Tight junctions TJ zonulae occludentes form a continuous, circumferential, beltlike structure at the boundary between the apical and the basolateral membrane domains in epithelial and endothelial cells. As the apicalmost part of the junctional complex Farquhar and Palade , the TJ forms a continuous, circumferential belt separating apical and basolateral plasma membrane domains, working as a barrier within the intercellular space and as a fence within the plasma membrane.
In recent years, information on the molecular composition of TJs, in particular their transmembrane molecules, has accumulated, forming the basis of our current understanding of the structure and function of TJs in molecular terms Fig. The morphology of TJs has been intensively analysed by freeze—fracture electron microscopy Staehelin ; Wolburg et al. The number and complexity of ramification of the network of TJ strands depends on the cell type, in sum yielding differences in permeability barrier function between different tissues Staehelin However, since a direct linear relationship between the complexity of the TJ strand network and the measured transepithelial electrical resistance TER could not unambiguousy be established for all cell types analysed, it was predicted that the strands might contain pores that fluctuate between open and closed conformations, suggesting that the TJ strands appear to be remarkably dynamic Claude Open image in new window.
Recent identification of the TJ-specific integral membrane proteins forwarded our understanding of TJ molecular composition in mammals: occludin ca. The occludin transmembrane domain spans the membrane four times with a short cytoplasmic N-terminus and an especially long corboxy-terminal cytoplasmic domain Fig. However, transfection of insect cells devoid of endogenous TJs with occludin cDNA surprisingly demonstrated that occludin is not by itself sufficient to form TJ strands but its expression merely produced focal homophilic adhesion sites Furuse et al.
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Moreover, disruption of both occludin alleles in embryonic stem cells did not prevent the formation of an effective diffusion barrier and the polarisation of epithelial cells, as shown by freeze—fracture analysis and TER assessment Saitou et al. It was thus concluded that occludin is not required for the formation of TJ strands. However, occludin appears to interact, directly or indirectly, with claudins and is recruited into the long strands formed by coexpression of claudin-1 and claudin-2 Furuse et al.
Balda et al. Using freeze—fracture electron microscopy and immunocytochemistry, they were able to attribute this increase in paracellular permeability to an altered distribution and membrane topology between neighbouring cells. Modulation of barrier function by cytokines Many cytokines have been shown to influence epithelial and endothelial TJ function and the actin cytoskeleton both in vivo and in vitro. Achler C, Filmer D, Merte C, Drenckhahn D Role of microtubules in polarized delivery of apical membrane proteins to the brush border of the intestinal epithelium.
Penn State Retina Research Group. Balda MS, Whitney JA, Flores C, Gonzalez S, Cereijido M, Matter K Functional dissociation of paracellular permeability and transepithelial electrical resistance and disruption of the apical-basolateral intramembrane diffusion barrier by expression of a mutant tight junction membrane protein. J Cereb Blood Flow Metab 1— Chang C, Werb Z The many faces of metalloproteases: cell growth, invasion, angiogenesis and metastasis. Claude P Morphological factors influencing transepithelial permeability: a model for the resistance of the zonula occludens.
Couraud PO Infiltration of inflammatory cells through brain endothelium. Cramer EB The ability of leukocytes to cross the tight junctions. In: Cerejido M ed Tight junctions. Neurology — PubMed Google Scholar. Dejana E, Spagnuolo R, Bazzoni G Interendothelial junctions and their role in the control of angiogenesis, vascular permeability and leukocyte transmigration. Ebnet K Organization of multiprotein complexes at cell—cell junctions. This issue Google Scholar.
Felinski EA, Antonetti DA Glucocorticoid regulation of endothelial cell tight junction gene expression: novel treatments for diabetic retinopathy. Ferrary E, Sterkers O Mechanisms of endolymph secretion. Implications for the mechanism of reovirus attachment. J Physiol Furuse M, Fujimoto K, Sato N, Hirase T, Tsukita S Overexpression of occludin, a tight junction-associated integral membrane protein, induces the formation of intracellular multilamellar bodies bearing tight junction-like structures.
Furuse M, Sasaki H, Fujimoto K, Tsukita S b A single gene product, claudin-1 or -2, reconstitutes tight junction strands and recruits occludin in fibroblasts. Furuse M, Sasaki H, Tsukita S Manner of interaction of heterogeneous claudin species within and between tight junction strands.
Gilcrease MZ, Guzman-Paz M Fine-needle aspiration of basaloid squamous carcinoma: a case report with review of differential diagnostic considerations. Brain — CrossRef Google Scholar. Gastroenterology — PubMed Google Scholar. Internal epithelia on the other hand more often rely on tight junctions for their barrier function. This kind of barrier is mostly formed by only one or two layers of cells.
It was long unclear whether tight cell junctions also play any role in the barrier function of the skin and similar external epithelia but recent research suggests that this is indeed the case. Epithelia are classed as "tight" or "leaky", depending on the ability of the tight junctions to prevent water and solute movement: .
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Tight junction Diagram of Tight junction. Van; Anderson, James M. Cold Spring Harbor Perspectives in Biology. Cold Spring Harb Perspect Biol. June American Journal of Physiology. Cell Physiology. August Tight junction structure and function: lessons from mutant animals and proteins".
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Gastrointestinal and Liver Physiology. Fluids and Barriers of the CNS. Davidson College. Retrieved The Journal of Cell Biology. Renal Physiology. Annals of the New York Academy of Sciences.