Active and passive involvement of claudins in the pathophysiology of intestinal inflammatory diseases.

Christian Barmeyer, Michael Fromm, Jörg-Dieter Schulzke

Pflugers Archiv : European journal of physiology 2017 Jan

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Intestinal inflammatory diseases, four of which are discussed here, are associated with alterations of claudins. In ulcerative colitis, diarrhea and antigen entry into the mucosa occurs. Claudin-2 is upregulated but data on other claudins are still limited or vary (e.g., claudin-1 and -4). Apart from that, tight junction changes contribute to diarrhea via a leak flux mechanism, while protection against antigen entry disappears behind epithelial gross lesions (erosions) and apoptotic foci. Crohn's disease is additionally characterized by a claudin-5 and claudin-8 reduction which plays an active role in antigen uptake already before gross lesions appear. In microscopic colitis (MC), upregulation of claudin-2 expression is weak and a reduction in claudin-4 may be only passively involved, while sodium malabsorption represents the main diarrheal mechanism. However, claudin-5 is removed from MC tight junctions which may be an active trigger for inflammation through antigen uptake along the so-called leaky gut concept. In celiac disease, primary barrier defects are discussed in the context of candidate genes as PARD3 which regulate cell polarity and tight junctions. The loss of claudin-5 allows small antigens to invade, while the reductions in others like claudin-3 are rather passive events. Taken together, the specific role of single tight junction proteins for the onset and perpetuation of inflammation and the recovery from these diseases is far from being fully understood and is clearly dependent on the stage of the disease, the background of the other tight junction components, the transport activity of the mucosa, and the presence of other barrier features like gross lesions, an orchestral interplay which is discussed in this article.

Citation

Christian Barmeyer, Michael Fromm, Jörg-Dieter Schulzke. Active and passive involvement of claudins in the pathophysiology of intestinal inflammatory diseases. Pflugers Archiv : European journal of physiology. 2017 Jan;469(1):15-26