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

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:

• celiac disease
• claudin-2
• Crohn's disease
• HIV
• IFNγ
• inflammatory bowel disease
• TNFα
• tight junction
• ulcerative colitis

Abbreviations:

• AP, activator protein
• CARD15, caspase recruitment domain-containing protein 15
• DSS, dextran sodium sulfate
• ECL, extracellular loop
• ERK, extracellular-regulated kinase
• gp, glycoprotein
• HIV, human immunodeficiency virus
• HNF, hepatocyte nuclear factor
• IBD, inflammatory bowel disease
• IFN, interferon
• 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
• Rho, ras homolog
• ROCK, Rho kinase
• STAT, signal transducers and activators of transcription
• Tat, trans-activator of transcription
• TEER, transepithelial electrical resistance
• TJ, tight junction
• TNBS, 2,4,6-trinitrobenzene sulfonic acid
• TNF, tumor necrosis factor
• Vpr, viral protein r; ZO, zonula occludens

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.