Downloaded from http://cshperspectives.cshlp.org/ on October 1, 2021 - Published by Cold Spring Harbor Laboratory Press Cell Biology of Tight Junction Barrier Regulation and Mucosal Disease Aaron Buckley and Jerrold R. Turner Departments of Pathology and Medicine (Gastroenterology), Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts 02115 Correspondence: [email protected] Mucosal surfaces are lined by epithelial cells. In the intestine, the epithelium establishes a selectively permeable barrier that supports nutrient absorption and waste secretion while preventing intrusion by luminal materials. Intestinal epithelia therefore play a central role in regulating interactions between the mucosal immune system and luminal contents, which include dietary antigens, a diverse intestinal microbiome, and pathogens. The paracellular space is sealed by the tight junction, which is maintained by a complex network of protein interactions. Tight junction dysfunction has been linked to a variety of local and systemic diseases. Two molecularly and biophysically distinct pathways across the intestinal tight junc- tion are selectively and differentially regulated by inflammatory stimuli. This review discusses the mechanisms underlying these events, their impact on disease, and the potential of using these as paradigms for development of tight junction-targeted therapeutic interventions. ucosal surfaces and the epithelial cells that adherens). The tight junction is a selectively Mline them are present at sites where tissues permeable barrier that generally represents the interface directly with the external environment rate-limiting step of paracellular transport. The or internal compartments that are contiguous adherens junction and desmosome provide es- with the external environment. Examples in- sential adhesive and mechanical properties that clude the gastrointestinal tract, the pulmonary contribute to barrier function but do not seal tree, and the genitourinary tract. In many cases the paracellular space. The tight junction is the the mucosa must balance the opposing goals of primary focus of this article. facilitating selective transport while also form- This article will focus on the gastrointestinal ing a barrier that restricts free exchange across tract. In part, this mirrors the state of knowledge the paracellular space. Crucial to both of these regarding tight junction biology within organ properties is the apical junctional complex. This systems. The gut has been studied in greatest structure, first described in 1963 (Farquhar and detail due to the relative accessibility of the Palade 1963), is composed of three junctions intestines by endoscopy, the highly ordered that, from apical to basal, are known as the tight architecture, and the remarkable physical and junction (zonula occludens), adherens junction biochemical stressors faced by the gastrointesti- (zonula adherens), and desmosome (macula nal mucosa. The latter include the most diverse Editors: Carien M. Niessen and Alpha S. Yap Additional Perspectives on Cell–Cell Junctions available at www.cshperspectives.org Copyright # 2018 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a029314 Cite this article as Cold Spring Harb Perspect Biol 2018;10:a029314 1 Downloaded from http://cshperspectives.cshlp.org/ on October 1, 2021 - Published by Cold Spring Harbor Laboratory Press A. Buckley and J.R. Turner microbiome of the body, peristalsis, and the MUCOSAL ANATOMY continuous washing of luminal contents over the surface. Within this context, the intestinal Mucosal surfaces share a common organization epithelia must direct selective active and passive (Fig. 1). In general, from lumen to serosa, vectorial transport of ions, nutrients, water, and mucosae are composed of an epithelial layer waste products (Ferraris and Diamond 1997; that sits on an acellular basement membrane. Kato and Romero 2011; Turner 2016). Finally, Beneath this, a loose connective tissue layer, it should be recognized that the gastrointestinal which may include blood vessels, lymphatics, tract is the primary site at which the immune immune cells, and other components, is termed system samples foreign materials that are essen- the lamina propria. Both epithelium and lami- tial to immune education (Chung et al. 2012; na propria contribute to the villus and crypt Hooper et al. 2012; Kim et al. 2016). This fact architecture of the small intestine (Fig. 1). The makes the regulatory systems that prevent aber- underlying muscularis mucosae represents the rant immune activation while promoting ap- deepest extent of the mucosa and separates propriate immune responses particularly im- the mucosa from the submucosa. The submu- portant within the gastrointestinal tract. It is cosa contains larger vessels, lymphatics, adipose therefore not surprising that almost any sub- tissue, and scattered immune cells. The submu- stantial defect in mucosal immune regulation cosa is thought to also cushion the mucosa from results in enterocolitis in experimental animals forces exerted during peristalsis. The muscularis and humans (Kuhn et al. 1993; Powrie et al. propria takes different forms depending on the 1994; d’Hennezel et al. 2009; Glocker et al. tissue. For example, the gastric muscularis pro- 2009; Hayes et al. 2015; Kiesler et al. 2015; pria contains three distinct sets of muscle fibers Mishima et al. 2015). with differing orientations, whereas the small AB Epithelium Lamina propria Muscularis mucosae Lymphoid follicle Brunner’s glands Submucosa Vessels Muscularis propria Myenteric plexus Figure 1. Small intestinal mucosal architecture. (A) Low magnification image of hematoxylin and eosin-stained section of normal human duodenum. Many of the structural features that are common throughout the gastro- intestinal tract and other mucosal surfaces can be appreciated. (B) Line diagram indicating specific structures that comprise the intestinal wall. The open spaces between fibers of the muscularis propria represent artefactual separation that occurred during tissue processing. (From Podolsky et al. 2015; reprinted, with permission from John Wiley & Sons #2015.) 2 Cite this article as Cold Spring Harb Perspect Biol 2018;10:a029314 Downloaded from http://cshperspectives.cshlp.org/ on October 1, 2021 - Published by Cold Spring Harbor Laboratory Press Tight Junctions and Mucosal Disease intestine and colon possess only longitudinal channels as well as basolateral ion transport and circumferential muscle fibers. In many, proteins necessary to support massive transcel- but not all sites, the muscularis propria is cov- lular chloride secretion that generates an ered by a thin layer of epithelium, the serosa. osmotic gradient to draw water into the Epithelial organization varies widely across lumen. Patients with cystic fibrosis, in which tissues. The airways (e.g., bronchioles), are the most prominent chloride channel, cystic fi- lined by a pseudostratified columnar epithelium brosis transmembrane conductance regulator with abundant apical cilia, whereas air spaces (CFTR), is defective, can develop intestinal (i.e., alveoli), are lined by a single layer of obstruction as a result of insufficient luminal squamous type 1 and cuboidal, surfactant-pro- hydration (Collins 1992). Conversely, CFTR ac- ducing type II epithelial cells. In contrast, the tivation by cholera toxin results in voluminous, transitional epithelium of the bladder is strati- watery diarrhea (Gabriel et al. 1994). As epithe- fied and contains specialized umbrella cells that lial cells exit the transit amplifying zone prolif- allow the bladder to distend as needed. The oral eration ceases and gene expression patterns cavity and esophagus are lined by stratified squ- change such that the same cells become special- amous epithelium, whereas the remainder of ized for nutrient absorption. Thus, in general the gastrointestinal tract is lined by a simple terms, the villus is an absorptive compartment (i.e., composed of a single layer), columnar whereas the crypt is secretory. epithelium. The organization of these epithelial cells and patterns of differentiation vary by site. INTESTINAL INTERCELLULAR JUNCTIONS For example, the stem and proliferative zone of the gastric mucosa is located within the Migration along the crypt-villus axis is accom- glandular neck, with the specialized parietal panied by expression of nutrient absorptive and chief cells located in the deep glands. In proteins, such as the apical sodium-glucose contrast, stem cells and Paneth cells are concen- cotransporter SGLT1(Hwang et al. 1991). Junc- trated within the base of intestinal glands (i.e., tional proteins contribute to this coordinated the crypts). migration and differentiation. For example, The small intestinal epithelium is composed E-cadherin overexpression within the intestinal of a single layer of columnar cells, many with a epithelium retards migration from crypt to well-developed microvillus brush border. At villus, suppresses proliferation, induces apopto- least two populations of stem cells are present sis within the crypt, and delays absorptive cell within the crypts, one that cycles actively and differentiation (Hermiston et al. 1996). Con- expresses the wnt pathway orphan receptor versely, disruption of E-cadherin function by Lgr5, and a second, quiescent population that transgenic expression of a dominant negative can replenish the Lgr5-positive pools after dam- N-cadherin accelerates migration and is accom- age (e.g., radiation) (Barker