Mechanisms and functional implications of intestinal barrier defects.
Intestinal epithelial barrier defects, or increased paracellular permeability, were first reported in patients with Crohn's disease (CD) over 25 years ago. Although increased permeability may herald relapse to active disease, suggesting that impaired barrier function may contribute to progression, limited understanding of the mechanisms that create barrier defects in CD has made it impossible to determine whether increased permeability is a cause or effect of disease. It is now clear that inflammatory cytokines trigger intestinal barrier defects acutely, by cytoskeletal contraction, or chronically, via modulation of tight junction protein expression. Both mechanisms cause barrier dysfunction, but their effects on paracellular size and charge selectivity differ. The clinical ramifications of this distinction are not yet clear. Recent data using in vivo models demonstrate that cytoskeletally mediated barrier dysfunction is sufficient to activate innate and adaptive components of mucosal immunity. Consistent with the presence of increased permeability in some healthy first-degree relatives of CD patients, these barrier defects are insufficient to cause disease in the absence of other stimuli. However, cytoskeletally mediated barrier defects are sufficient to accelerate onset and increase severity of experimental inflammatory bowel disease. Thus, inflammatory cytokines can cause barrier defects and, conversely, barrier defects can activate the mucosal immune system. This raises the possibility that restoration of barrier function may be therapeutic in CD. Consistent with this hypothesis, emerging data indicate that inhibition of cytoskeletally mediated barrier dysfunction may be able to prevent disease progression. Barrier restoration may, therefore, represent a non-immunosuppressive approach to achieving or maintaining disease remission.
Shen
Le
L
Department of Pathology, The University of Chicago, Chicago, Ill. 60637, USA.
Su
Liping
L
Turner
Jerrold R
JR
D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D007413:Intestinal Mucosa / Q000473:pathology* / Q000503:physiopathology*; D009219:Myosin-Light-Chain Kinase / Q000378:metabolism; D019108:Tight Junctions / Q000378:metabolism / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D014409:Tumor Necrosis Factor-alpha; D009219:Myosin-Light-Chain Kinase