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 junction 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

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Cell Biology of Tight Junction Barrier Regulation and Mucosal Disease

Tight Junction Structure and Function Revisited

Mucosal barriers separate self from non-self and are essential for life. These barriers, which are the first line of defense against external pathogens, are formed by epithelial cells and the substances they secrete. Rather than an absolute barrier, epithelia at mucosal surfaces must allow selective paracellular flux that discriminates between solutes and water while preventing the passage of bacteria and toxins. In vertebrates, tight junctions seal the paracellular space; flux across the tight junction can occur through two distinct routes that differ in selectivity, capacity, molecular composition and regulation. Dysregulation of either pathway can accompany disease. A third, tight-junction-independent route that reflects epithelial damage can also contribute to barrier loss during disease. In this Cell Science at a Glance article and accompanying poster, we present current knowledge on the molecular components and pathways that establish this selectively permeable barrier and the interactions that lead to barrier dysfunction during disease.

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The mucosal barrier at a glance

Tight junctions (TJs) establish the epithelial barrier and are thought to form a membrane fence to regulate epithelial polarity, although the roles of TJs in epithelial polarity remain controversial. Claudins constitute TJ strands in conjunction with the cytoplasmic scaffolds ZO-1 and ZO-2 and play pivotal roles in epithelial barrier formation. However, how claudins and other TJ membrane proteins cooperate to organize TJs remains unclear. Here, we systematically knocked out TJ components by genome editing and show that while ZO-1/ZO-2-deficient cells lacked TJ structures and epithelial barriers, claudin-deficient cells lacked TJ strands and an electrolyte permeability barrier but formed membrane appositions and a macromolecule permeability barrier. Moreover, epithelial polarity was disorganized in ZO-1/ZO-2-deficient cells, but not in claudin-deficient cells. Simultaneous deletion of claudins and a TJ membrane protein JAM-A resulted in a loss of membrane appositions and a macromolecule permeability barrier and in sporadic epithelial polarity defects. These results demonstrate that claudins and JAM-A coordinately regulate TJ formation and epithelial polarity.

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Claudins and JAM-A coordinately regulate tight junction formation and epithelial polarity

Tension-Dependent Stretching Activates ZO-1 to Control the Junctional Localization of Its Interactors

Epithelia within tubular organs form and expand lumens. Failure of these processes can result in serious developmental anomalies. Although tight junction assembly is crucial to epithelial polarization, the contribution of specific tight junction proteins to lumenogenesis is undefined. Here, we show that ZO-1 (also known as TJP1) is necessary for the formation of single lumens. Epithelia lacking this tight junction scaffolding protein form cysts with multiple lumens and are defective in the earliest phases of polarization, both in two and three dimensions. Expression of ZO-1 domain-deletion mutants demonstrated that the actin-binding region and U5-GuK domain are crucial to single lumen development. For actin-binding region, but not U5-GuK domain, mutants, this could be overcome by strong polarization cues from the extracellular matrix. Analysis of the U5-GuK binding partners shroom2, α-catenin and occludin showed that only occludin deletion led to multi-lumen cysts. Like ZO-1-deficiency, occludin deletion led to mitotic spindle orientation defects. Single lumen formation required the occludin OCEL domain, which binds to ZO-1. We conclude that ZO-1-occludin interactions regulate multiple phases of epithelial polarization by providing cell-intrinsic signals that are required for single lumen formation.

ZO-1 interactions with F-actin and occludin direct epithelial polarization and single lumen specification in 3D culture.

Background Retroperitoneal and rectus sheath hematomas can occur spontaneously. There is a lack of research about the disease progression, optimal treatment strategies and the need for surgical intervention. Our study investigated their outcomes and management. Study design Adult patients admitted during a one-year period with non-traumatic retroperitoneal or rectus sheath hematomas were retrospectively identified. Biographical, hospital-course, and outcome data were extracted. Results 99 patients were included; median age was 73-years (IQR 61–80). 88 patients were on an anticoagulant or antiplatelet agent. Warfarin and intravenous heparin being the most commonly utilized agents (42% and 36.4%, respectively). All 99 patients were diagnosed by CT scan. 79 patients received some sort of blood product (79.8% PRBC, 43.4% FFP, 17% platelets), and 26 patients were in hemorrhagic shock. 17 patients underwent angiography and/or angioembolization. Neither anticoagulation in general nor any specific agent was associated with the need for blood product transfusion or angiography. 13 patients died but none were attributable to the hematoma. Conclusion Both hematomas are usually self-limiting and rarely require surgical intervention. A subset may require angioembolization.

Michael H. Warren

Papers

ZO-1 interactions with F-actin and occludin direct epithelial polarization and single lumen specification in 3D culture.

Contemporary management of spontaneous retroperitoneal and rectus sheath hematomas.