The Proceedings of the American Thoracic Society 1:38-41 (2004)
© 2004 The American Thoracic Society
The Role of Claudins in Determining Paracellular Charge Selectivity
Christina M. Van Itallie and
James M. Anderson
Departments of Medicine and Cell and Molecular Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
Correspondence and requests for reprints should be addressed to James M. Anderson, M.D., Ph.D., The University of North Carolina at Chapel Hill, Department of Cell & Molecular Physiology, 266 MSRB, Chapel Hill, NC 27599-7545. E-mail: jandersn{at}med.unc.edu
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ABSTRACT
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Tight junctions create regulated barriers in the paracellular space between epithelial cells, including those of the airway and alveolus. Junctions vary widely throughout the body in their electrical resistance and, to some extent, in their ionic charge selectivity. Paracellular differences complement transcellular transport to define overall water, ion, and solute movements. A large family of transmembrane proteins called claudins has recently been implicated in creating the variable properties of the junction. Here we highlight the evidence that claudins are functional components of the barrier. Supportive data include evidence from deletion of selected claudins in mice, human genetic diseases of claudins 14 and 16, and direct experimental tests of the hypothesis that the extracellular charged residues on claudins influence the passage of ions through the junction. Alterations in claudin expression profiles may contribute to epithelial lung dysfunction during infection and inflammation. Much work remains to be done in the molecular characterization of tight junctions in the lung in normal physiology and during pathologic processes.
Key Words: tight junction • paracellular • claudins • epithelia • transport
In this short review, we will highlight the variable nature of the tight-junction selectivity in different epithelia, recent insights into the molecular structure of the junction, and some of our own recent experimental results implicating a family of tight-junction transmembrane proteins called the claudins in creating charge-selective pores in the junction. Finally, we speculate on areas of future research in lung biology that will be important to pursue in order to understand normal lung epithelial physiology and alterations in disease.
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PARACELLULAR PROPERTIES VARY AMONG EPITHELIA
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Barrier characteristics of the tight junction vary widely among epithelia with respect to overall electrical resistance and, to a lesser extent, in ionic charge selectivity (Table 1) (1, 2). As commonly defined, so-called "leaky" epithelia are less than about 1,000 
· cm2 and have more than 50% of the conductance occurring through the tight junction (Table 1) (1, 3). Leaky epithelia do not support significant gradients of ions or osmolytes and establish low transepithelial electrical potentials. These characteristics correlate with the ability to transport large volumes of isosmotic fluid. Paracellular charge selectivity is an import factor in leaky epithelia because of the opportunities to influence forward movement of counter ions or back-leak of the transported ion through the tight junction. So-called "tight" epithelia, like those of the collecting duct of the nephron and amphibian skin, can maintain high electroosmotic gradients and potential differences but, because they allow little paracellular transport, the charge selectivity is more difficult to measure and is less relevant.
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TABLE 1. Electrophysiologic characteristics of some epithelia and culture epithelial cell lines. both resistance and paracellular charge selectivity are variable properties.
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PROTEIN COMPONENTS OF THE TIGHT JUNCTION
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Much has been learned about the molecular proteins of the tight junction over the last decade, and they can be grouped into several functional categories. They include proteins that are involved in generating apical–basolateral cell polarity, signal transduction, scaffolding of transmembrane proteins and attaching of these proteins to the actin–cytoskeleton, and finally the transmembrane proteins themselves; for reviews, see (4–6). This latter group presently includes occludin, the small family of junction adhesion molecules (7) and the large family of claudins (8–10). The weight of evidence shows that the claudins govern the magnitude of the barrier, its ionic charge selectivity (11–14), and perhaps size selectivity (15).
The barrier is formed at the apical end of the lateral cell surfaces, where adjacent cells come into close contact. They do this at a variable number of spots, or "kisses" (two are shown in Figure 1B). In freeze-fracture electron microscopy, the contact points correspond to continuous rows of transmembrane proteins. For example, in the lobar bronchus, the junction contact region is approximately 0.5 µm deep and very complicated, including up to 11 strands (16). It was recently established that claudins constitute the fibril rows and adhere across the paracellular space to create the barrier (Figure 1A) (17).
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Figure 1. (A) Ciliated pseudostratified columnar epithelium of the bronchus forms a barrier between the airway and internal environment. Tight junctions at the apical end of the lateral surface seal the paracellular spaces between cells. (B) Molecular model of the tight-junction and functional categories of proteins. The paracellular space is sealed by contacts between the transmembrane proteins of the claudin family. The categories of cytoplasmic proteins include those involved in scaffolding the transmembrane proteins and coupling them to the actin cytoskeleton, establishing cell polarity and signal transduction. For review of individual proteins, see Reference 5.
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CLAUDINS CREATE THE BARRIER
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There are a large number of claudin genes (6). Over 20 genes have been detected in a single mammalian species, and there also exist a number of more distantly related gene products originally characterized in different biologic contexts. One of these, PMP22 (peripheral myelin protein-22) has been located in tight junctions, opening the possibility of additional, distantly related barrier proteins that contribute to the junctions (18). Some tight junctions express several different claudins (19) while others express a single type (20). It is assumed that the barrier properties of each junction are explained by the collective or ensemble properties of the claudins expressed.
Several lines of evidence implicate claudins in determining the barrier properties. First, there are many claudins and they show different expression profiles among epithelia (19). Second, when individual claudins have been expressed in cultured Madin Darby-Canine Kidney (MDCK) epithelial monolayers, they alter the electrical resistance; some increase (21, 22) and others reduce resistance (14). In one case, claudin-4 was shown to increase resistance in a dose-dependent fashion, further supporting a causal relationship (21). MDCK cells have been a popular model for many years as a generic epithelial line because they are well polarized, develop intact tight junctions, and are readily transfectable. They are used with the assumption that biologic insights from a renal line can be applied to other cell types, including those in the lung, although generalizability should be confirmed. Third, the phenotypes of mice from which specific claudins were deleted support their role in forming barriers. A dramatic example is observed in the claudin-1 knockout mice, which die shortly after birth from dehydration (10). Claudin-1 is the major claudin in the epidermis and presumably provides a barrier against insensible water loss from the skin. Finally, the human phenotypes of mutations in claudins 14 and 16 not only suggest a role in resistance but also in creating ionic charge-selective barriers. Claudin-16 is expressed in the thick ascending loop of Henle. Normally, the tubule develops a positive electrical potential with respect to the interstitial space, driving cations through the junction, out of the tubule, and back to the blood. When claudin-16 is missing, magnesium ions do not return from the tubule to the blood, are lost in the urine, and patients develop hypomagnesaemia (12). Early in the disease, tubules remain histologically normal, and it has been proposed that claudin-16 (a.k.a., paracellin-1) provides a cation-selective channel through the fibrils. Claudin-14 is expressed in tight junctions of the inner ear. Mutations cause deafness (23). The pathophysiologic explanation remains obscure but may be due to the inability of junctions lacking claudin-14 to restrict paracellular movement of potassium ions.
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CLAUDINS CREATE IONIC CHARGE SELECTIVITY OF PARACELLULAR TRANSPORT.
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These observations led us to hypothesize and directly test whether claudins have different ionic charge selectivities. As a model system we produced clonal lines of MDCK epithelial cells, where specific claudins were under the control of a doxycycline-regulated promoter. By removing doxycycline from the growth media, the claudin was expressed and cell lines could be compared with the same clones without induction. When claudin-4 was expressed in MDCK cells, we observed a several-fold decrease in conductance (21). The dilution potential for NaCl was next measured across the monolayers to detect any change in charge selectivity following expression of claudin-4. Expression of claudin-4 correlated in a dose-dependent fashion with a decrease in Na+ permeability, whereas that for Cl- was unaffected. The increase in resistance induced by claudin-4 could be entirely accounted for by the selective discrimination against Na+.
This result led us to compare the distribution of charged amino acid side chains within the two extracellular domains of claudins. Some residues are identical in all claudins and many are conserved, while the total number of positive and negative residues is also variable. The simplest model is that the charged residues are positioned in the paracellular space where they influence passage of ions. Consistent with this, when the positively charged residue at position 46 in the first domain of claudin-4 is mutated to a negatively charged residue, it shows reduced discrimination against Na+ (13).
To further test the simple electrostatic charged-pore model, we created MDCK cell lines expressing mutant forms of claudin-15 (Figure 2A) (13). Claudin-15 has a large number of negative residues in the first extracellular domain, leading us to predict it would favor passage of Na+ relative to Cl-. Because MDCK cells are, at baseline, very Na+-selective (Table 1), we predicted that expression of the wild-type protein would not change the charge selectivity. We created charge-reversing mutations, singly and in combinations, for residues 46, 55, and 64 (Figure 2A) with the prediction that some sites might cause a discrimination against Na+ relative to Cl-. As revealed by dilution potential studies in Figure 2B, the charge at position 46 had no effect on charge selectivity; however, both positions 55 and 64 had strong, additive effects. These results suggest that claudins create the charge selectivity of tight junctions through the electrostatic effects of their extracellular, charged amino acids. Subsequent studies, using the same cultured cell model, have shown that claudins 8 (24), 14 (25) and 11 (26) decrease paracellular conductance and discriminate against cations. In contrast, claudins 2 and 15 increase the permeability for Na+ (26). These ionic charge selectivities can be rationalized as being due to the charges on the first extracellular loop. Much work remains to determine all the residues involved in defining selectivity and to define the three-dimensional structures of the channels.
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Figure 2. (A) Membrane topology of human claudin-15 predicting four transmembrane helices, cytoplasmic N- and C-termini, and two extracellular loops. Three negatively charged residues are present on the first extracellular loop: E46 (glutamate 46), D55 (aspartate 55), and E64 (glutamate 64). Using site-directed mutagenesis, these were changed to positively charged residues, singly and in combinations, m1 (E46K-lysine), m2 (D44R-arginine), and m3 (E64K-lysine). (B) Dilution potential on MDCK monolayers before (white) and after (black) induction of specific claudin-15 mutations. Positive dilution potentials indicate that PNa is greater than PCl. A charge reversal at position 46(m1) had no effect, while changes at positions 55 or 64 both reversed the selectivity, and their effects were additive. Adapted with permission from Colegio and coworkers, Am J Physiol Cell Physiol. 2002;283:C142.
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FUTURE STUDIES: PARACELLULAR TRANSPORT IN THE LUNG
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The human lung contains a large surface area of transporting epithelium, divided into the alveolar and airway epithelia (Figure 1A). The alveolar surface is the larger of the two, and is estimated to be 70–75 m2 (27). Gas exchange across the alveolar epithelium, as well as mucociliary clearance and air hydration along the airways, are critically dependent on a regulated layer of surface liquid. Its ionic composition and volume are carefully regulated in health (28) and altered in diseases like cystic fibrosis (CF) (29) or infections. Studies on excised tissue and cultured airway cells demonstrate the ability to both absorb and secrete depending on the stimulus (reviewed in [28]). As distal lung fluid is moved toward the bronchi by mucociliary mechanisms, significant amounts of fluid must be absorbed because the surface area progressively decreases in moving up each segmentation. Thus, in vivo, the normal direction in the airways is absorption to maintain the proper surface layer for mucociliary clearance (30). This high level of absorption is consistent with airway epithelia being moderately leaky. The reported electrical resistance of cultured airway cells can be higher than most measurements on tissue, raising the concern that culture conditions alter tight-junction properties (see Table 1 for typical examples). In any case, the selectivity of tight junctions and their potential alteration in disease is expected to have a major impact on the composition and volume of the airway surface fluid in both the airways and the alveoli (31).
At present, we have only a rudimentary understanding of the molecular components of tight junctions in the lung. A first step to understanding their role in normal transport and disease would be to define the total profile of claudins and their distribution among the different epithelia of the lung. Recent reports document expression of claudins 1, 3, 4, 5, 7 (32), and 18 (33) in bronchi and bronchioli, and of claudins 3, 4, and 5 in alveoli in situ (34). A significant caveat is that reagents for the many other claudins were not available for these studies. Like other complex epithelia, the lung expresses many claudins, although it remains unknown whether they show regional variations in expression. Next, we must learn more about the characteristics of each claudin to correlate their position with epithelial properties in each part of the lung. We can expect that each claudin will define different levels of resistance and different charge selectivity. An important goal will be to determine whether the expression of claudins is altered in disease and contributes to alterations in transport. For example, are there genetic diseases of tight junctions in the lung? Are claudin profiles altered in inflammation, malignancy, infection or asthma? Do they change in response to alterations in transcellular transport (e.g., CF)?
The possibility that tight junctions can alter their charge selectivity as a compensatory adaptation to disease was recently reported in studies in intestine from patients with CF (35). Neonates with CF can develop dehydration of intestinal contents and inspissated intestinal obstruction (meconium ileus). This is theorized to result from the lack of CF transmembrane regulator–dependent secretion in the face of ongoing Na+-dependent fluid absorption, resulting in hyperabsorption. The group led by John Fordtran (Baylor College of Medicine) recently reported that hyperabsorption in adult jejunum cannot be demonstrated (35). There is a marked decrease is paracellular Cl- permeability. During Na+–glucose cotransport, the absence of passive Cl- absorption completely blocked net Na+ absorption and reduced glucose-stimulated water absorption by 66%. This adaptation would tend to correct the tendency to dehydrate intestinal contents. They speculate the change in charge selectivity may result from a change in the claudin profile.
A number of articles have shown that claudin levels in the intestine and cultured intestinal cells are regulated by proinflammatory cytokines (36, 37). Potentially, these changes could contribute to the transport derangements (i.e., diarrhea) observed in inflammatory bowel diseases (38). Support for a similar response in the lung comes from the recent observation that the proinflammatory cytokine interleukin-1ß induces a change in paracellular charge selectivity (39). Exposure of primary human airway cultures to interleukin-1ß for 72 hours induced a two-fold increase in both PCl/PNa (permeability ratio of Cl- to Na+) and monolayer conductance, interpreted as a selective increase in paracellular permeability to Cl-. Interleukin-1ß levels are known to be increased in the sputum of patients with CF, suggesting that if PCl were increased by interleukin-1ß in patients with CF, this might contribute to hyperabsorption of Na+, Cl-, and water observed in the epithelia. This would lead to decreased surface fluid, decreased mucociliary clearance, and increased tendency to develop bacterial infection.
The recognition that claudins contribute to paracellular selectivity has opened multiple new approaches to understanding the role of tight junctions in normal lung biology and in diseases.
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FOOTNOTES
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Supported by the National Institutes of Health, grants RO1 DK 45134 and PO1 DK55389, and by the University of North Carolina.
(Received in original form June 19, 2003; accepted in final form September 29, 2003)
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ABSTRACT
PARACELLULAR PROPERTIES VARY...
