Epithelial Claudin Proteins and Their Role in Gastrointestinal Diseases
David Y. Kim
Department of Pediatrics, Gastrointestinal Eosinophilic Diseases Program, Section of Pediatric Gastroenterology, Hepatology and Nutrition, University of Colorado School of Medicine, Aurora, CO
Digestive Health Institute, Children's Hospital Colorado, Aurora, CO
Department of Medicine, Mucosal Inflammation Program, University of Colorado School of Medicine, Aurora, CO
Search for more papers by this authorCorresponding Author
Glenn T. Furuta
Department of Pediatrics, Gastrointestinal Eosinophilic Diseases Program, Section of Pediatric Gastroenterology, Hepatology and Nutrition, University of Colorado School of Medicine, Aurora, CO
Digestive Health Institute, Children's Hospital Colorado, Aurora, CO
Department of Medicine, Mucosal Inflammation Program, University of Colorado School of Medicine, Aurora, CO
Address correspondence and reprint requests to Joanne C. Masterson, MD, Department of Biology, Maynooth University, Co. Kildare, Ireland W23 F2H6 (e-mail: [email protected]); Glenn T. Furuta, MD, Children's Hospital Colorado, Aurora, CO 80016 (e-mail: [email protected]).Search for more papers by this authorNathalie Nguyen
Department of Pediatrics, Gastrointestinal Eosinophilic Diseases Program, Section of Pediatric Gastroenterology, Hepatology and Nutrition, University of Colorado School of Medicine, Aurora, CO
Digestive Health Institute, Children's Hospital Colorado, Aurora, CO
Department of Medicine, Mucosal Inflammation Program, University of Colorado School of Medicine, Aurora, CO
Search for more papers by this authorEisuke Inage
Department of Pediatrics, Gastrointestinal Eosinophilic Diseases Program, Section of Pediatric Gastroenterology, Hepatology and Nutrition, University of Colorado School of Medicine, Aurora, CO
Department of Pediatrics and Adolescent Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan
Search for more papers by this authorCorresponding Author
Joanne C. Masterson
Department of Pediatrics, Gastrointestinal Eosinophilic Diseases Program, Section of Pediatric Gastroenterology, Hepatology and Nutrition, University of Colorado School of Medicine, Aurora, CO
Digestive Health Institute, Children's Hospital Colorado, Aurora, CO
Department of Medicine, Mucosal Inflammation Program, University of Colorado School of Medicine, Aurora, CO
Department of Biology, Maynooth University, Co., Kildare, Ireland
Address correspondence and reprint requests to Joanne C. Masterson, MD, Department of Biology, Maynooth University, Co. Kildare, Ireland W23 F2H6 (e-mail: [email protected]); Glenn T. Furuta, MD, Children's Hospital Colorado, Aurora, CO 80016 (e-mail: [email protected]).Search for more papers by this authorDavid Y. Kim
Department of Pediatrics, Gastrointestinal Eosinophilic Diseases Program, Section of Pediatric Gastroenterology, Hepatology and Nutrition, University of Colorado School of Medicine, Aurora, CO
Digestive Health Institute, Children's Hospital Colorado, Aurora, CO
Department of Medicine, Mucosal Inflammation Program, University of Colorado School of Medicine, Aurora, CO
Search for more papers by this authorCorresponding Author
Glenn T. Furuta
Department of Pediatrics, Gastrointestinal Eosinophilic Diseases Program, Section of Pediatric Gastroenterology, Hepatology and Nutrition, University of Colorado School of Medicine, Aurora, CO
Digestive Health Institute, Children's Hospital Colorado, Aurora, CO
Department of Medicine, Mucosal Inflammation Program, University of Colorado School of Medicine, Aurora, CO
Address correspondence and reprint requests to Joanne C. Masterson, MD, Department of Biology, Maynooth University, Co. Kildare, Ireland W23 F2H6 (e-mail: [email protected]); Glenn T. Furuta, MD, Children's Hospital Colorado, Aurora, CO 80016 (e-mail: [email protected]).Search for more papers by this authorNathalie Nguyen
Department of Pediatrics, Gastrointestinal Eosinophilic Diseases Program, Section of Pediatric Gastroenterology, Hepatology and Nutrition, University of Colorado School of Medicine, Aurora, CO
Digestive Health Institute, Children's Hospital Colorado, Aurora, CO
Department of Medicine, Mucosal Inflammation Program, University of Colorado School of Medicine, Aurora, CO
Search for more papers by this authorEisuke Inage
Department of Pediatrics, Gastrointestinal Eosinophilic Diseases Program, Section of Pediatric Gastroenterology, Hepatology and Nutrition, University of Colorado School of Medicine, Aurora, CO
Department of Pediatrics and Adolescent Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan
Search for more papers by this authorCorresponding Author
Joanne C. Masterson
Department of Pediatrics, Gastrointestinal Eosinophilic Diseases Program, Section of Pediatric Gastroenterology, Hepatology and Nutrition, University of Colorado School of Medicine, Aurora, CO
Digestive Health Institute, Children's Hospital Colorado, Aurora, CO
Department of Medicine, Mucosal Inflammation Program, University of Colorado School of Medicine, Aurora, CO
Department of Biology, Maynooth University, Co., Kildare, Ireland
Address correspondence and reprint requests to Joanne C. Masterson, MD, Department of Biology, Maynooth University, Co. Kildare, Ireland W23 F2H6 (e-mail: [email protected]); Glenn T. Furuta, MD, Children's Hospital Colorado, Aurora, CO 80016 (e-mail: [email protected]).Search for more papers by this authorThe study was supported by NIH 1K24DK100303 (G.T.F.) and K01-DK106315 (J.C.M.).
The authors report no conflicts of interest.
ABSTRACT
Our bodies are protected from the external environment by mucosal barriers that are lined by epithelial cells. The epithelium plays a critical role as a highly dynamic, selective semipermeable barrier that separates luminal contents and pathogens from the rest of the body and controlling the absorption of nutrients, fluid and solutes. A series of protein complexes including the adherens junction, desmosomes, and tight junctions function as the principal barrier in paracellular diffusion and regulators of intracellular solute, protein, and lipid transport. Tight junctions are composed of a series of proteins called occludins, junctional adhesion molecules, and claudins that reside primarily as the most apical intercellular junction. Here we will review one of these protein families, claudins, and their relevance to gastrointestinal and liver diseases.
REFERENCES
- 1.Kim TI. The role of barrier dysfunction and change of claudin expression in inflammatory bowel disease. Gut Liver 2015; 9: 699–700.
- 2.Garcia-Hernandez V, Quiros M, Nusrat A. Intestinal epithelial claudins: expression and regulation in homeostasis and inflammation. Ann N Y Acad Sci 2017; 1397: 66–79.
- 3.Angelow S, Ahlstrom R, Yu AS. Biology of claudins. Am J Physiol Renal Physiol 2008; 295: F867–F876.
- 4.Turksen K, Troy TC. Barriers built on claudins. J Cell Sci 2004; 117 (pt 12): 2435–2447.
- 5.Furuse M, Hirase T, Itoh M, et al. Occludin: a novel integral membrane protein localizing at tight junctions. J Cell Biol 1993; 123 (6 pt 2): 1777–1788.
- 6.Martin-Padura I, Lostaglio S, Schneemann M, et al. Junctional adhesion molecule, a novel member of the immunoglobulin superfamily that distributes at intercellular junctions and modulates monocyte transmigration. J Cell Biol 1998; 142: 117–127.
- 7.Furuse M, Fujita K, Hiiragi T, et al. Claudin-1 and -2: novel integral membrane proteins localizing at tight junctions with no sequence similarity to occludin. J Cell Biol 1998; 141: 1539–1550.
- 8.Van Itallie CM, Anderson JM. Claudins and epithelial paracellular transport. Annu Rev Physiol 2006; 68: 403–429.
- 9.Suzuki H, Tani K, Fujiyoshi Y. Crystal structures of claudins: insights into their intermolecular interactions. Ann N Y Acad Sci 2017; 1397: 25–34.
- 10.Krause G, Winkler L, Mueller SL, et al. Structure and function of claudins. Biochim Biophys Acta 2008; 1778: 631–645.
- 11.Furuse M, Hata M, Furuse K, et al. Claudin-based tight junctions are crucial for the mammalian epidermal barrier: a lesson from claudin-1-deficient mice. J Cell Biol 2002; 156: 1099–1111.
- 12.Rahner C, Mitic LL, Anderson JM. Heterogeneity in expression and subcellular localization of claudins 2, 3, 4, and 5 in the rat liver, pancreas, and gut. Gastroenterology 2001; 120: 411–422.
- 13.D'Souza T, Sherman-Baust CA, Poosala S, et al. Age-related changes of claudin expression in mouse liver, kidney, and pancreas. J Gerontol A Biol Sci Med Sci 2009; 64: 1146–1153.
- 14.Laurila JJ, Karttunen T, Koivukangas V, et al. Tight junction proteins in gallbladder epithelium: different expression in acute acalculous and calculous cholecystitis. J Histochem Cytochem 2007; 55: 567–573.
- 15.Nemeth Z, Szasz AM, Tatrai P, et al. Claudin-1, -2, -3, -4, -7, -8, and -10 protein expression in biliary tract cancers. J Histochem Cytochem 2009; 57: 113–121.
- 16.Shigetomi K, Ikenouchi J. Regulation of the epithelial barrier by post-translational modifications of tight junction membrane proteins. J Biochem 2018; 163: 265–272.
- 17.Ikenouchi J, Matsuda M, Furuse M, et al. Regulation of tight junctions during the epithelium-mesenchyme transition: direct repression of the gene expression of claudins/occludin by Snail. J Cell Sci 2003; 116 (pt 10): 1959–1967.
- 18.Watson AJ, Duckworth CA, Guan Y, et al. Mechanisms of epithelial cell shedding in the mammalian intestine and maintenance of barrier function. Ann N Y Acad Sci 2009; 1165: 135–142.
- 19.Amasheh M, Fromm A, Krug SM, et al. TNFalpha-induced and berberine-antagonized tight junction barrier impairment via tyrosine kinase, Akt and NFkappaB signaling. J Cell Sci 2010; 123 (pt 23): 4145–4155.
- 20.Poniatowski ŁA, Wojdasiewicz P, Gasik R, et al. Transforming growth factor beta family: insight into the role of growth factors in regulation of fracture healing biology and potential clinical applications. Mediators Inflamm 2015; 2015: 137823.
- 21.Pierucci-Alves F, Yi S, Schultz BD. Transforming growth factor beta 1 induces tight junction disruptions and loss of transepithelial resistance across porcine vas deferens epithelial cells. Biol Reprod 2012; 86: 36.
- 22.Nguyen N, Fernando SD, Biette KA, et al. TGF-beta1 alters esophageal epithelial barrier function by attenuation of claudin-7 in eosinophilic esophagitis. Mucosal Immunol 2018; 11: 415–426.
- 23.Ota T, Fujii M, Sugizaki T, et al. Targets of transcriptional regulation by two distinct type I receptors for transforming growth factor-beta in human umbilical vein endothelial cells. J Cell Physiol 2002; 193: 299–318.
- 24.Shiou SR, Singh AB, Moorthy K, et al. Smad4 regulates claudin-1 expression in a transforming growth factor-beta-independent manner in colon cancer cells. Cancer Res 2007; 67: 1571–1579.
- 25.Halder SK, Rachakonda G, Deane NG, et al. Smad7 induces hepatic metastasis in colorectal cancer. Br J Cancer 2008; 99: 957–965.
- 26.Khan N, Asif AR. Transcriptional regulators of claudins in epithelial tight junctions. Mediators Inflamm 2015; 2015: 219843.
- 27.Barmeyer C, Schulzke JD, Fromm M. Claudin-related intestinal diseases. Semin Cell Dev Biol 2015; 42: 30–38.
- 28.Zeissig S, Burgel N, Gunzel D, et al. Changes in expression and distribution of claudin 2, 5 and 8 lead to discontinuous tight junctions and barrier dysfunction in active Crohn's disease. Gut 2007; 56: 61–72.
- 29.Tsukita S, Furuse M, Itoh M. Multifunctional strands in tight junctions. Nat Rev Mol Cell Biol 2001; 2: 285–293.
- 30.Al-Sadi R, Ye D, Boivin M, et al. Interleukin-6 modulation of intestinal epithelial tight junction permeability is mediated by JNK pathway activation of claudin-2 gene. PLoS One 2014; 9: e85345.
- 31.Gunzel D, Fromm M. Claudins and other tight junction proteins. Compr Physiol 2012; 2: 1819–1852.
- 32.Bücker R, Schumann M, Amasheh S, Yu A, et al. Claudins in intestinal function and disease. Current Topics in Membranes. Amsterdam, The Netherlands: Academic Press; 2010. 195–227.
10.1016/S1063-5823(10)65009-0 Google Scholar
- 33.Saeedi BJ, Kao DJ, Kitzenberg DA, et al. HIF-dependent regulation of claudin-1 is central to intestinal epithelial tight junction integrity. Mol Biol Cell 2015; 26: 2252–2262.
- 34.Schumann M, Richter JF, Wedell I, et al. Mechanisms of epithelial translocation of the alpha(2)-gliadin-33mer in coeliac sprue. Gut 2008; 57: 747–754.
- 35.Schulzke JD, Bentzel CJ, Schulzke I, et al. Epithelial tight junction structure in the jejunum of children with acute and treated celiac sprue. Pediatr Res 1998; 43 (4 pt 1): 435–441.
- 36.Bjarnason I, Peters TJ, Veall N. A persistent defect in intestinal permeability in coeliac disease demonstrated by a 51Cr-labelled EDTA absorption test. Lancet 1983; 1: 323–325.
- 37.Duerksen DR, Wilhelm-Boyles C, Parry DM. Intestinal permeability in long-term follow-up of patients with celiac disease on a gluten-free diet. Dig Dis Sci 2005; 50: 785–790.
- 38.Van Elburg RM, Uil JJ, Mulder CJ, et al. Intestinal permeability in patients with coeliac disease and relatives of patients with coeliac disease. Gut 1993; 34: 354–357.
- 39.Schumann M, Kamel S, Pahlitzsch ML, et al. Defective tight junctions in refractory celiac disease. Ann N Y Acad Sci 2012; 1258: 43–51.
- 40.Schumann M, Gunzel D, Buergel N, et al. Cell polarity-determining proteins Par-3 and PP-1 are involved in epithelial tight junction defects in coeliac disease. Gut 2012; 61: 220–228.
- 41.Szakal DN, Gyorffy H, Arato A, et al. Mucosal expression of claudins 2, 3 and 4 in proximal and distal part of duodenum in children with coeliac disease. Virchows Arch 2010; 456: 245–250.
- 42.Orlando RC. The integrity of the esophageal mucosa. Balance between offensive and defensive mechanisms. Best Pract Res Clin Gastroenterol 2010; 24: 873–882.
- 43.Neumann H, Monkemuller K, Fry LC, et al. Intercellular space volume is mainly increased in the basal layer of esophageal squamous epithelium in patients with GERD. Dig Dis Sci 2011; 56: 1404–1411.
- 44.Monkemuller K, Wex T, Kuester D, et al. Role of tight junction proteins in gastroesophageal reflux disease. BMC Gastroenterol 2012; 12: 128.
- 45.Bjorkman EV, Edebo A, Oltean M, et al. Esophageal barrier function and tight junction expression in healthy subjects and patients with gastroesophageal reflux disease: functionality of esophageal mucosa exposed to bile salt and trypsin in vitro. Scand J Gastroenterol 2013; 48: 1118–1126.
- 46.Jovov B, Que J, Tobey NA, et al. Role of E-cadherin in the pathogenesis of gastroesophageal reflux disease. Am J Gastroenterol 2011; 106: 1039–1047.
- 47.Liacouras CA, Furuta GT, Hirano I, et al. Eosinophilic esophagitis: updated consensus recommendations for children and adults. J Allergy Clin Immunol 2011; 128: 3.e6–20.e6. quiz 21-22.
- 48.Abdulnour-Nakhoul SM, Al-Tawil Y, Gyftopoulos AA, et al. Alterations in junctional proteins, inflammatory mediators and extracellular matrix molecules in eosinophilic esophagitis. Clin Immunol 2013; 148: 265–278.
- 49.Steed E, Balda MS, Matter K. Dynamics and functions of tight junctions. Trends Cell Biol 2010; 20: 142–149.
- 50.Katzka DA, Tadi R, Smyrk TC, et al. Effects of topical steroids on tight junction proteins and spongiosis in esophageal epithelia of patients with eosinophilic esophagitis. Clin Gastroenterol Hepatol 2014; 12: 1824.e1–1829.e1.
- 51.Doshi A, Khamishon R, Rawson R, et al. IL-9 alters epithelial barrier and E-cadherin in eosinophilic esophagitis. J Pediatr Gastroenterol Nutr 2019; 68: 225–231.
- 52.Tanaka H, Imasato M, Yamazaki Y, et al. Claudin-3 regulates bile canalicular paracellular barrier and cholesterol gallstone core formation in mice. J Hepatol 2018; 69: 1308–1316.
- 53.Zeisel MB, Dhawan P, Baumert TF. Tight junction proteins in gastrointestinal and liver disease. Gut 2018; [Epub ahead of print].
- 54.Hewitt KJ, Agarwal R, Morin PJ. The claudin gene family: expression in normal and neoplastic tissues. BMC Cancer 2006; 6: 186.
- 55.Katoh M, Katoh M. CLDN23 gene, frequently down-regulated in intestinal-type gastric cancer, is a novel member of CLAUDIN gene family. Int J Mol Med 2003; 11: 683–689.
- 56.Niimi T, Nagashima K, Ward JM, et al. claudin-18, a novel downstream target gene for the T/EBP/NKX2.1 homeodomain transcription factor, encodes lung- and stomach-specific isoforms through alternative splicing. Mol Cell Biol 2001; 21: 7380–7390.
- 57.Tamura A, Yamazaki Y, Hayashi D, et al. Claudin-based paracellular proton barrier in the stomach. Ann N Y Acad Sci 2012; 1258: 108–114.
- 58.Wang H, Yang X. The expression patterns of tight junction protein claudin-1, -3, and -4 in human gastric neoplasms and adjacent non-neoplastic tissues. Int J Clin Exp Pathol 2015; 8: 881–887.
- 59.Lameris AL, Huybers S, Kaukinen K, et al. Expression profiling of claudins in the human gastrointestinal tract in health and during inflammatory bowel disease. Scand J Gastroenterol 2013; 48: 58–69.
- 60.Holmes JL, Van Itallie CM, Rasmussen JE, et al. Claudin profiling in the mouse during postnatal intestinal development and along the gastrointestinal tract reveals complex expression patterns. Gene Expr Patterns 2006; 6: 581–588.
- 61.Sapone A, Lammers KM, Casolaro V, et al. Divergence of gut permeability and mucosal immune gene expression in two gluten-associated conditions: celiac disease and gluten sensitivity. BMC Med 2011; 9: 23.
- 62.Lu Z, Ding L, Lu Q, et al. Claudins in intestines: distribution and functional significance in health and diseases. Tissue Barriers 2013; 1: e24978.
- 63.Fujita H, Chiba H, Yokozaki H, et al. Differential expression and subcellular localization of claudin-7, -8, -12, -13, and -15 along the mouse intestine. J Histochem Cytochem 2006; 54: 933–944.
- 64.Gunzel D, Yu AS. Claudins and the modulation of tight junction permeability. Physiol Rev 2013; 93: 525–569.