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. 2015 Apr 3;3(1-2):e977176.
doi: 10.4161/21688370.2014.977176. eCollection 2015.

Claudin-2 as a mediator of leaky gut barrier during intestinal inflammation

J Luettig  1 , R Rosenthal  1 , C Barmeyer  1 , J D Schulzke  1
Affiliations

Claudin-2 as a mediator of leaky gut barrier during intestinal inflammation

J Luettig et al. Tissue Barriers. .

Abstract

The epithelial tight junction determines the paracellular water and ion movement in the intestine and also prevents uptake of larger molecules, including antigens, in an uncontrolled manner. Claudin-2, one of the 27 mammalian claudins regulating that barrier function, forms a paracellular channel for small cations and water. It is typically expressed in leaky epithelia like proximal nephron and small intestine and provides a major pathway for the paracellular transport of sodium, potassium, and fluid. In intestinal inflammation (Crohn's disease, ulcerative colitis), immune-mediated diseases (celiac disease), and infections (HIV enteropathy), claudin-2 is upregulated in small and large intestine and contributes to diarrhea via a leak flux mechanism. In parallel to that upregulation, other epithelial and tight junctional features are altered and the luminal uptake of antigenic macromolecules is enhanced, for which claudin-2 may be partially responsible through induction of tight junction strand discontinuities.

Keywords: AP, activator protein; CARD15, caspase recruitment domain-containing protein 15; Crohn's disease; DSS, dextran sodium sulfate; ECL, extracellular loop; ERK, extracellular-regulated kinase; HIV; HIV, human immunodeficiency virus; HNF, hepatocyte nuclear factor; IBD, inflammatory bowel disease; IFN, interferon; IFNγ; IL, interleukin; JAM, junctional adhesion molecule; JNK, c-jun N-terminal kinase; LPS, lipopolysaccharides; MAPK, mitogen-activated protein kinase; MDCK, Madine Darby canine kidney; MLC, myosin light chain; NFκB, nuclear factor kappa B; NOD2, nucleotide-binding oligomerization domain-containing protein 2; PI3K, phosphatidyl-inositol-3-kinase; ROCK, Rho kinase; Rho, ras homolog; STAT, signal transducers and activators of transcription; TEER, transepithelial electrical resistance; TJ, tight junction; TNBS, 2,4,6-trinitrobenzene sulfonic acid; TNF, tumor necrosis factor; TNFα; Tat, trans-activator of transcription; Vpr, viral protein r; ZO, zonula occludens; celiac disease; claudin-2; gp, glycoprotein; inflammatory bowel disease; tight junction; ulcerative colitis.

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Figures

Figure 1.
Figure 1.
Summary of claudin-2 regulation. Figure is based on references. See text for detailed description.
Figure 2.
Figure 2.
Freeze fracture electron microscopy of epithelial tight junctions from the jejunum of controls (left) and acute celiac disease patients with villus atrophy (right) obtained from Schulzke et al. Significant reduction in the number or horizontally oriented strands and the depth of the tight junctional strand network was observed. Additionally, strand discontinuities appeared in celiac disease.
See this image and copyright information in PMC

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