A major component of many inflammatory diseases of mucosal surfaces, particularly in the intestine, is migration of large numbers of neutrophils (PMN) across the epithelium and accumulation within a lumen. In such conditions, disease symptoms are complex but directly related to leukocyte effects on the epithelial barrier and epithelial cell function. While much has been learned about mechanisms of leukocyte emigration from the circulation, much less is known about the receptors that regulate leukocyte interactions with the intestinal epithelium. In our studies, we have shown that a sequential series of adhesive steps are necessary for PMN to traverse the epithelium in a polarized manner that begins with interactions with the basolateral membrane and ends at the level of the apical or luminal membrane. However, many of the details of the transepithelial migration cascade and functional consequences of such remain poorly understood despite the clear link to many inflammatory diseases. This proposal will focus on functional consequences of PMN interactions with specific receptors at the level of the tight junction and apical/luminal epithelial membrane. We will extend recently obtained evidence linking binding interactions between PMN expressed JAM like protein (JAML) and the tight junction associated coxsackie and adenovirus receptor (CAR) with pro-inflammatory effects on epithelial homeostasis. Our studies also suggest that expression of the prototypic JAM protein family member termed JAM-A on leukocytes and epithelial cells is important in preventing pathologic inflammation in the intestine, however the relative contributions of epithelial and leukocyte expressed JAM-A to regulating intestinal mucosal homeostasis are not defined. Mechanisms and relative contributions of JAM-A in leukocytes and epithelial cells to development of experimental colitis will be explored. We have also determined that at late stages of the PMN transepithelial migration response there are binding interactions between PMN and the apical epithelial membrane mediated by specific glycan epitopes displayed on the transmembrane protein CD44v6. Such binding interactions result in epithelial functional responses that positively regulate epithelial barrier function. Details of the mechanisms behind such PMN interactions with epithelial cells are lacking despite the potential importance of resultant epithelial signaling responses in promoting mucosal health and healing. Experiments in this proposal will provide insights into these important issues as well as new ideas for the development of agents that might be used as anti-inflammatories in a tissue targeted manner as well as for enhanced mucosal wound healing.
Disease symptoms in a number of pathologic conditions such as ulcerative colitis are linked to excessive migration of acute inflammatory cells termed neutrophils (PMN) across a specialized epithelium that lines the intestine to form a protective barrier. The goal of this proposal is to define receptors that regulate migration of PMN across intestinal epithelium with and to understand epithelial responses to PMN transmigration. We will specifically focus on PMN interactions with proteins associated with regulation of intestinal barrier termed junctional adhesion molecules as well as interactions with receptors on the luminal aspect of the intestinal epithelium. Understanding the relationships between the above regulatory molecules, epithelial barrier, and inflammation may provide new therapeutic strategies for conditions such as inflammatory bowel disease.
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