Control of neutrophil inflammation at mucosal surfaces by secreted epithelial products

Abstract

The human intestine is a large and delicately balanced organ, responsible for efficiently absorbing nutrients and selectively eliminating disease-causing pathogens. The gut architecture consists of a single layer of epithelial cells that forms a barrier against the food antigens and resident microbiota within the lumen. This barrier is augmented by a thick layer of mucus on the luminal side and an underlying lamina propria containing a resident population of immune cells. Attempted breaches of the intestinal barrier by pathogenic bacteria result in the rapid induction of a coordinated innate immune response that includes release of antimicrobial peptides, activation of pattern recognition receptors, and recruitment of various immune cells. In recent years, the role of epithelial cells in initiating this immune response has been increasingly appreciated. In particular, epithelial cells are responsible for the release of a variety of factors that attract neutrophils, the body's trained bacterial killers. In this review we will highlight recent research that details a new understanding of how epithelial cells directionally secrete specific compounds at distinct stages of the inflammatory response in order to coordinate the immune response to intestinal microbes. In addition to their importance during the response to infection, evidence suggests that dysregulation of these pathways may contribute to pathologic inflammation during inflammatory bowel disease. Therefore, a continued understanding of the mechanisms by which epithelial cells control neutrophil migration into the intestine will have tremendous benefits in both the understanding of biological processes and the identification of potential therapeutic targets.

Keywords: MRP2; Salmonella; eicosanoids; hepoxilin; intestinal inflammation; lipid chemoattractant; lipoxygenase; neutrophil migration.

Figure 1

The HXA₃ inflammatory pathway. (A) Infection of the epithelial cell (blue) surface by pathogenic bacteria (red) induces signaling through pattern recognition receptors, including TLR5, and activation of NFkB, leading to pro-inflammatory responses including basolateral secretion of IL-8. An IL-8 gradient forms that is imprinted in the subepithelial extracellular matrix, and IL-8 binds to endothelial cell (green) surface in order to recruit neutrophils out of the vasculature. Meanwhile, bacterial infection activates phospholipase A2-mediated liberation of arachidonic acid from the plasma membrane. Arachidonic acid is converted to HXA₃ via the action of 12/15-lipoxygenase and secreted from the apical surface via the action of MRP2. HXA₃ released into the lumen diffuses across the paracellular junction between epithelial cells to create a concentration gradient that will recruit neutrophils across the epithelium. (B) Neutrophils extravasate through endothelial cells into lamina propria, where they sense the HXA₃ gradient, and migrate across the epithelial paracellular junction into the lumen. There, they encounter bacteria and release effectors including ROS and proteases, which can also lead to collateral damage to epithelial cells (dying cell shown in orange).