Inflammatory bowel disease is a chronic, unremitting disorder whose etiology is linked to triggering events, including viral infections, that lead to immunoregulatory dysfunction in some genetically susceptible people. The mucosal inflammation that typifies this disabling disorder is linked to interactions among immune cells, nonimmune cells, and the extracellular matrix (ECM). More specifically, mucosal lymphoid cells release mediators that stimulate juxtaposed mucosal smooth muscle cells (M-SMCs), causing cell hyperplasia, cytokine production, and adhesion molecule-mediated leukocyte binding. We recently reported a novel, alternative mechanism of M-SMC-leukocyte interaction whereby virus-infected/viral analog-induced M-SMCs elaborate hyaluronan that engages CD44 expressed by mononuclear leukocytes. We hypothesize that hyaluronan, produced by virus- infected M-SMCs, results in recruitment of leukocytes to the gut mucosa where the resultant activated leukocytes elaborate inflammatory mediators that propagate the inflammatory response. Using a validated model that integrates each of the key components, we propose to use morphologic and mechanistic approaches to elucidate the structural configurations, regulatory aspects, and activating parameters of this unique interaction. Confocal microscopy, molecular biology techniques, leukocyte binding assays, and protein and carbohydrate electrophoresis will be used to: 1) investigate the production of hyaluronan and the mechanism by which it is incorporated into ECM structures that selectively bind leukocytes; 2) study the binding proteins that organize unique adhesive hyaluronan structures into the ECM and directly or indirectly influence adhesion; and 3) determine the consequences of leukocyte binding to these M-SMC-produced hyaluronan structures. Directed study of this novel binding phenomenon that is characteristic of, but not likely limited to inflamed intestinal mucosa will introduce new avenues of investigation that might culminate in future target-directed therapies.
