Regulation of Intestinal Epithelial Permeability by Tight Junctions
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Cell. Mol. Life Sci. (2013) 70:631–659 DOI 10.1007/s00018-012-1070-x Cellular and Molecular Life Sciences REVIEW Regulation of intestinal epithelial permeability by tight junctions Takuya Suzuki Received: 3 April 2012 / Revised: 19 June 2012 / Accepted: 21 June 2012 / Published online: 11 July 2012 Ó Springer Basel AG 2012 Abstract The gastrointestinal epithelium forms the BT-IgSF Brain- and testis-specific immunoglobulin boundary between the body and external environment. It superfamily effectively provides a selective permeable barrier that C10 Capric acid limits the permeation of luminal noxious molecules, such C12 Lauric acid as pathogens, toxins, and antigens, while allowing the CAR Coxsacki and adenovirus receptor appropriate absorption of nutrients and water. This selec- CD Crohn’s disease tive permeable barrier is achieved by intercellular tight CHO Chinese hamster ovary junction (TJ) structures, which regulate paracellular per- CPE Clostridium perfringen enterotoxin meability. Disruption of the intestinal TJ barrier, followed DHA Docosahexaenoic acid by permeation of luminal noxious molecules, induces a DSS Dextran sodium sulfate perturbation of the mucosal immune system and inflam- ECN Escherichia coli Nissle1917 mation, and can act as a trigger for the development of EGF Epidermal growth factor intestinal and systemic diseases. In this context, much EHEC Enterohemorrhagic Escherichia coli effort has been taken to understand the roles of extracel- EPA Eicosapentaenoic acid lular factors, including cytokines, pathogens, and food EPEC Enteropathogenic Escherichia coli factors, for the regulation of the intestinal TJ barrier. Here, ERK Extracellular signal-regulated kinase I discuss the regulation of the intestinal TJ barrier together ESAM Endothelial selective adhesion molecule with its implications for the pathogenesis of diseases. EspF Escherichia coli secreted protein F GPCR G-protein-coupled receptor Keywords Tight junction Á Intestinal epithelium Á HA/P Hemagglutinin/protease Cytokine Á Pathogen Á Nutrient HS/R Hemorrhagic shock and resuscitation IBD Inflammatory bowel disease Abbreviations IBS Irritative bowel syndrome AJ Adherens junction IFN Interferon ALD Alcoholic liver disease Ig Immunoglobulin AMPK AMP activated protein kinase IL Interleukin BBDP Biobreeding diabetes-prone JAM Junctional adhesion molecule BiCM Conditioned medium of Bifidobacterium LA Linolec acid infantis LCFA Long chain fatty acid LIGHT Lymphotoxin-like inducible protein L. plantarum Lactobacillus plantarum T. Suzuki (&) L. rhamnosus Lactobacillus rhamnosus Department of Biofunctional Science and Technology, Graduate MAGUK Membrane-associated guanylate kinase School of Biosphere Science, Hiroshima University, 1-4-4, Kagamiyama, Higashi-Hiroshima 739-8528, Japan homolog e-mail: [email protected] MAP Mitochondrial-associated protein 123 632 T. Suzuki MCFA Medium chain fatty acid Normal barrier Impaired barrier MEK Mitogen-activated protein kinase MLC Myosin light chain Bacterial products and MLCK Myosin light chain kinase dietary antigens NFjB Nuclear factor-jB Intestinal lumen PAR Proteinase activated receptor PDZ Post-synaptic density 95/Drosophila discs large/zona-occludens 1 Tight junction PI3K Phosphatidyl inositol-3 kinase PK Protein kinase PKA cAMP-dependent kinase Epithelial cells PP Protein phosphatase PPAR Peroxisome proliferator-activated receptor PTP Protein tyrosine phosphatase Macrophages ROCK Rho-associated kinase T cells SCFA Short chain fatty acid Lamina propria Dendritic cells SH Src homology T1D Type I diabetes T cells Immune activation TER Transepithelial electrical resistance Inflammation TGF Transforming growth factor TJ Tight junction Fig. 1 Barrier function of intestinal tight junctions (TJs). The TLR Toll-like receptor intestinal epithelium provides a physical barrier to luminal bacteria, toxins, and antigens. The barrier is organized by different barrier TNF Tumor necrosis factor components, including the TJs. The TJs regulate the paracellular TNFR TNF-a receptor passages of ions, solutes, and water between adjacent cells. Luminal TPN Total parenteral nutrition noxious macromolecules cannot penetrate the epithelium because VDR Vitamin D receptor of the TJ barrier; however, TJ barrier impairment allows the passage of noxious molecules, which can induce the excessive activation of ZO Zonula occludens mucosal immune cells and inflammation. Therefore, intestinal barrier ZOT Zonula occludens toxin defects are associated with the initiation and development of various intestinal and systemic diseases Introduction intercellular communication, but does not determine para- cellular permeability [6, 7]. The TJs encircle the apical ends The gastrointestinal epithelium forms the body’s largest of the lateral membranes of epithelial cells and determine the interface with the external environment. The epithelium selective paracellular permeability to solutes [4, 5]. In this allows the absorption of nutrients while providing a physical regard, the TJs provide both a barrier to noxious molecules barrier to the permeation of proinflammatory molecules, and a pore for the permeation of ions, solutes, and water as such as pathogens, toxins, and antigens, from the luminal appropriate. TJs are multiple protein complexes composed environment into the mucosal tissues and circulatory system of transmembrane proteins, such as claudins and occludin, (see Fig. 1). The epithelial cells create this selective per- and a wide spectrum of cytosolic proteins. The modification meability by two pathways: the transcellular and the of TJ barrier function and paracellular permeability is paracellular pathway. The transcellular pathway is involved dynamically regulated by various extracellular stimuli and is in the absorption and transport of nutrients, including sugars, closely associated with our health and susceptibility disease amino acids, peptides, fatty acids, minerals, and vitamins. As [8–10]. TJ barrier disruption and increased paracellular the cell membrane is impermeable, this process is predom- permeability, followed by permeation of luminal proin- inantly mediated by specific transporters or channels located flammatory molecules, can induce activation of the mucosal on the apical and basolateral membranes [1–3]. The para- immune system, resulting in sustained inflammation and cellular pathway is associated with transport in the tissue damage. Evidence from basic science and clinical intercellular space between the adjacent epithelial cells. It is studies indicate that the intestinal TJ barrier has a critical role regulated by an apical junctional complex, which is com- in the pathogenesis of intestinal and systemic diseases [8, 10, posed of tight junctions (TJs) and adherence junctions (AJs) 11]. Under pathophysiological conditions, pro-inflamma- [4–7]. The AJ, along with desmosomes, provides strong tory cytokines, antigens, and pathogens contribute to barrier adhesive bonds between the epithelial cells and also aids impairment [9, 12]. In contrast, food factors and nutrients 123 Regulation of intestinal tight junction 633 also participate in intestinal TJ regulation, and some of these Lumen could be developed as preventive and therapeutic tools for defective barrier-associated diseases [13, 14]. Experimen- tally, TJ barrier integrity and permeability in intestinal tissues and cells are evaluated by measurement of transepi- Claudins thelial electrical resistance (TER) and the paracellular Myosin passage of small molecules, such as mannitol, dextran, and Occludin ZO-1 inulin. This review first describes the molecular structure of F-actin intestinal TJs, then summarizes the regulation of the intes- Tight JAM-A junction tinal TJ structure and permeability by extracellular factors, MLCK such as cytokines, growth factors, pathogens, nutrients, and ZO-1 food factors, and finally discusses the involvement of α-catenin intestinal TJs in health and disease pathogenesis. E-cadherin Adherens junction Molecular structure of TJs β-catenin Desmoglein TJs are multiple protein complexes located at the apical Desmosome ends of the lateral membranes of intestinal epithelial cells Keratin (see Fig. 2). They regulate the paracellular passage of ions, solutes, and water, and are also known to act as a fence to Desmoplakin Desmocolin maintain cell polarity by blocking the free diffusion of proteins and lipids between the apical and basolateral Enterocyte domains of the plasma membrane [8, 11]. Four integral transmembrane proteins, occludin [15], claudins [16], Fig. 2 Molecular structure of the intercelluar junction of intestinal epithelial cells. The intercellular junctions of intestinal epithelial cells junctional adhesion molecule (JAM) [17], and tricellulin are sealed by different protein complexes, including TJs, adherens [18], have been identified, with the claudin family con- junctions (AJs), and desmosomes. The TJs, multiple protein com- sisting of at least 24 members. The extracellular domains plexes, locate at the apical ends of the lateral membranes of intestinal of the transmembrane proteins form the selective barrier by epithelial cells. The TJ complex consists of transmembrane and intracellular scaffold proteins. The extracellular loops of the trans- hemophilic and heterophilic interactions with the adjacent membrane proteins (occludin, claudins, JAMs, and tricellulin) create cells [19]. The intracellular domains of these transmem- a permselective barrier in the paracellular pathways by hemophilic brane proteins interact with cytosolic scaffold proteins,