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1 Department of Pediatrics, Division of Gastroenterology and Nutrition and 2 Department of Medicine, Division of Respirology, The University of Toronto, Toronto, Ontario, Canada M5S 1A8; 3 Department of Medicine, Division of Respirology, The University of Sherbrooke, Sherbrooke, Quebec, J1H 5N4; 4 Faculty of Dentistry, University of Toronto, CIHR Group in Periodontal Physiology and 5 Department of Pathobiology and Laboratory Medicine, The University of Toronto, Toronto, Ontario, Canada M5S 1A8
Neutrophil-mediated injury to gut epithelium may lead
to disruption of the epithelial barrier function with consequent organ dysfunction, but the mechanisms of this are incompletely characterized. Because the epithelial apical junctional complex, comprised of tight
and adherens junctions, is responsible in part for this barrier
function, we investigated the effects of neutrophil transmigration on
these structures. Using a colonic epithelial cell line, we observed
that neutrophils migrating across cell monolayers formed clusters that
were associated with focal epithelial cell loss and the creation of
circular defects within the monolayer. The loss of epithelial cells was
partly attributable to neutrophil-derived proteases, likely elastase,
because it was prevented by elastase inhibitors. Spatially delimited
disruption of epithelial junctional complexes with focal loss of
E-cadherin, 
-catenin, and zonula occludens 1 was observed adjacent
to clusters of transmigrating neutrophils. During neutrophil
transmigration, fragments of E-cadherin were released into the apical
supernatant, and inhibitors of neutrophil elastase prevented this
proteolytic degradation. Addition of purified leukocyte elastase also
resulted in release of E-cadherin fragments, but only after opening of
tight junctions. Taken together, these data demonstrate that
neutrophil-derived proteases can mediate spatially delimited disruption
of epithelial apical junctions during transmigration. These processes
may contribute to epithelial loss and disruption of epithelial barrier
function in inflammatory diseases.
leukocyte; inflammation; adherens junctions; adhesion molecules; epithelium; inflammatory mediators; tight junctions
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