Interactions of neutrophils with epithelial cells: lessons from the intestine

Active inflammatory processes in organs lined by columnar epithelial cells are often characterized by abundant neutrophil migration. To reach an epithelial surface, neutrophils must leave the vasculature and cross the interstitium where signals may be generated that influence migration and/or epithelial function. Subsequently neutrophils migrate across epithelial linings by impaling intercellular junctions between epithelial cells and, in doing so, diminish the ability of epithelial linings to serve as a barrier. Decreased barrier function brought about by neutrophil migration across epithelia appears to be a reversible process after the removal of the chemotactic stimulus. The molecular events underlying neutrophil-epithelial interactions are at present poorly understood. With recent information regarding neutrophil-endothelial interactions, it has been possible to better understand issues of neutrophil interactions with epithelial cells. In general, there appear to be different rules governing the interaction of neutrophils with endothelial cells as compared with epithelial cells. Neutrophil migration across endothelial monolayers involves a series of at least three steps, each regulated by glycoproteins expressed on the cellular surface. In considering neutrophil-epithelial interactions, the single common denominator is the requirement for surface expression of neutrophil beta 2 integrins, and specifically CD11b/18, as shown by functional inhibition through the use of antibodies to neutrophil beta 2 integrins and the use of neutrophils from patients lacking the beta-chain of this integrin. An understanding of the regulation of neutrophil-epithelial interactions, although in its infancy, appears to involve inflammatory cytokines. Recent in vivo evidence suggests that interferon-gamma production at the level of the intestine may correlate with the regulation of neutrophil-epithelial interactions in vitro by interferon-gamma. Finally, considerable evidence exists that neutrophils may contribute significantly to fluid transport during inflammatory diseases such as secretory diarrhea. When placed in contact with epithelial monolayers, activated neutrophils bring about the transport of ions, with concomitant water loss across epithelial surfaces. This transport process brought about by the presence of neutrophils is generated by a metabolite produced and secreted from neutrophils. This metabolite was originally termed neutrophil-derived secretagogue and has recently been identified as 5'-AMP. The mechanism of 5'-AMP action on epithelial cell ion transport is discussed.