Neutrophil—epithelial interactions, and efforts to down-regulate them, in inflammatory bowel disease

Abstract

The histopathological hallmark of the active flares of inflammatory bowel disease (IBD) is the transepithelial migration of neutrophils (so-called crypt abscess). The fact that such active intestinal inflammation correlates with patient symptoms suggests a major role for neutrophil transmigration in causing the epithelial dysfunction characteristic of IBD. Transmigrating neutrophils disrupt epithelial barrier function exposing subepithelial cells to the noxious milieu of the intestinal lumen. Further, these neutrophils can directly induce the intestinal epithelia to secrete chloride ions into the lumen — an event which serves as the basis for secretory diarrhoea. It has recently become clear that intestinal epithelial cells may play an active role in orchestrating neutrophil movement to the lumen. Since the event of neutrophil transepithelial migration characteristic of active IBD is identical to that seen in response to epithelial surface colonization by pathogens, it is likely that one can gain insight into the former event by better understanding the latter circumstance. We have used the model of Salmonella typhimurium—intestinal epithelial interaction for this purpose. We have shown that, in response to detection of S. typhimurium, epithelia secrete chemokines in a polarized manner such that neutrophils are directed through the lamina propria and subsequently across the epithelia. S. typhimurium activates these epithelial cell proinflammatory signalling pathways by inducing an increase in cytoplasmic [Ca²⁺] that leads to activation of the transcription factor NF-KB. Since such evolutionarily conserved defence mechanisms might be aberrantly triggered to result in the same cellular responses in the absence of pathogens (for example in IBD) we are now defining mechanisms to down-regulate these proinflammatory signals that direct intestinal inflammation. The arachidonate metabolite lipoxin A4 (LXA4) is an endogenously biosynthesized anti-inflammatory eicosanoid. Receptors for LXA₄ are expressed on both intestinal epithelial cells and neutrophils. Further, we find LXA₄ and its analogues down-regulate the above molecular events which define intestinal