The tight junction in inflammatory disease: communication breakdown

Abstract

The intestinal epithelium restricts free passage of toxic and infectious molecules from the gut lumen while allowing selective paracellular absorption across the tight junction. Inflammatory bowel disease (IBD) patients demonstrate a loss of tight junction barrier function, increased pro-inflammatory cytokine production, and immune dysregulation; however, the relationship between these events is incompletely understood. Although tight junction barrier defects are insufficient to cause experimental IBD, mucosal immune activation is altered in response to increased epithelial permeability. Thus, an evolving model suggests that barrier dysfunction may predispose or enhance disease progression and therapies targeted to specifically restore the barrier function may provide an alternative or supplement to immunology-based therapies.

Figure 1. Cytokine regulation of epithelial barrier function

Pro-inflammatory cytokines such as TNF, IL-1β, and LIGHT promote barrier dysfunction by inhibiting transcription of junction proteins and inducing cytoskeleton-mediated redistribution of tight junction proteins. These cytokines promote transcription of MLCK, which when activated phosphorylates myosin II, resulting in reorganization of tight junction proteins, including endocytic removal from the apical junctional complex.

Figure 2. Tight junction morphology is altered in immune-mediated diarrhea

Mice were injected intraperitoneally with anti-CD3 antibody to induce acute immune-mediated diarrhea which is accompanied by increased TNF and IFNγ production. Immunofluorescence localization of ZO-1 and occludin in small small intestinal epithelium was assessed before or 3 hours after anti-CD3 treatment. While ZO-1 distribution appears unchanged in transverse sections, when viewed en face, ZO-1 staining at the junction appears thinner and concentrated more at tricellular junctions with anti-CD3 treatment. Similarly, occludin internalization into vesicles is seen in both transverse and en face sections following treatment with anti-CD3 [44]. (From Clayburgh et al. J Clin Invest 115: 2702-15, 2005, with permission.)

Figure 3. Increased paracellular permeability accelerates immune-mediated colitis

CD4⁺CD45Rb^hi (triangles) or CD4⁺CD25Rb^lo (circles) T-cells were adoptively transferred into RAG1−/− mice (red symbols) or RAG1^−/− mice expressing constitutively active MLCK (yellow symbols). RAG1^−/−/CA-MLCK recipients transferred with CD4⁺CD45Rb^hi T-cells exhibited increased weight loss and mortality post-transfer compared to RAG1^−/− recipients [52]. (From Su et al. Gastroenterol 136: 551-63, 2009, with permission.)