Inflammatory diseases of the intestinal tract are a major health concern both in the United States and around the world. Every year in the U.S. alone, millions are affected by transient, food-born, pathogen-induced bowel disease and chronic inflammatory bowel diseases like Crohn's and Colitis, all of which result in significant suffering and lost productivity. Active inflammation of the intestine is characterized by an innate immune response at the epithelial surface resulting in the secretion of pro-inflammatory factors and neutrophil movement into the intestinal lumen. During inflammation, the epithelial cells lining the intestine play a critical role by rapidly responding to pathogens with the polar secretion of pro-inflammatory chemokines, specifically apical pathogen-elicited-epithelial-chemoattractant (PEEC) and basolateral IL-8. This proposal aims to understand the role of epithelial cell polarity in modulating bacterial-induced chemoattractant release and neutrophil transmigration at the site of infection. Currently very little is known about the signal transduction pathway(s) responsible for eliciting the innate immune response to pathogenic bacterial like Salmonella typhimurium. The Toll-like receptor 5 (TLR5), localized in the basolateral membrane of intestinal epithelia, is segregated from the intestinal flora and is responsible for sensing pathogenic bacterial invasion. This proposal seeks to identify and characterize the protein-based sorting signals by which polarized epithelial cells target TLR5 delivery to the basolateral membrane. TLR5 has been implicated in signaling the nuclear events necessary for the synthesis and secretion of IL-8, however, it is unclear whether or not it may play a role in the apical secretion of PEEC. Thus, another goal of this research is to examine in detail the nuclear signaling pathway leading to IL-8 and PEEC secretion. The epithelial orchestration of neutrophil movement and the subsequent effects of the recruited neutrophils on epithelial function are paramount to the symptoms of inflammatory bowel disease, disruption of the epithelial tight junction and secretory diarrhea. Recent studies indicate that members of the Rho family of small GTPases, RhoA and Racl, regulate the development of cell-cell contacts and the polarized distribution of membrane proteins as well as both the gate and fence functions of the tight junction. This proposal will also examine the role of the Rho GTPases on the transepithelial migration of neutrophils.
| Sun, Jun; Fegan, Pamela E; Desai, Anjali S et al. (2007) Flagellin-induced tolerance of the Toll-like receptor 5 signaling pathway in polarized intestinal epithelial cells. Am J Physiol Gastrointest Liver Physiol 292:G767-78 |
