Neutrophils (PMN) act as a “double edged sword” in promoting both tissue injury and repair. Analysis of intestinal tissue from patients with active inflammatory bowel diseases (IBD) show increased numbers of PMN that infiltrate the intestinal epithelium and remain in intimate contact with apical intestinal epithelial cell (IEC) membranes, thus continuously engaging apical ligands. While the link between PMN TEM and epithelial barrier function has been established, PMN interactions with apical IEC ligands, and the effects of these interactions on epithelial homeostasis and wound repair are not known. One such ligand is intracellular adhesion molecule 1 (ICAM-1). Its expression is significantly increased in inflamed epithelium and is restricted to the apical surface, however its roles in PMN-IEC interactions and epithelial function are not clear. Our preliminary data suggest that PMN after completion of TEM are retained on the luminal epithelial membrane through binding to ICAM-1. PMN adhesion to the apical epithelial membrane through binding to ICAM-1 inhibits PMN apoptosis, resulting in prolonged life span of PMN. PMN engagement of ICAM-1 leads to decreased epithelial integrity and an induction of proliferative signaling facilitating epithelial wound repair. Thus, the overall goal of this proposal is to define the mechanisms and the signaling events initiated by PMN engagement of ICAM-1 that lead to increased epithelial permeability, PMN TEM and epithelial repair. In Aim 1 we will define the signaling events downstream of ICAM-1 ligation that increase epithelial permeability to facilitate enhanced PMN TEM, using in-vitro and in-vivo models of PMN TEM, supplemented with molecular and protein approaches, and advanced multi-photon intravital imaging. In Aim 2 we will define the role for ICAM-1 in regulation of epithelial homeostasis and wound repair using in-vitro scratch wound assays and novel in-vivo models of acute injury and inflammation, including colonoscopic biopsy-wound and DSS-induced colonic mucosal injury. Experiments outlined in the current proposal will shed new light on mechanisms regulating PMN TEM and retention at the mucosal surfaces, and aid in identification of specific molecules that link PMN-epithelial cell interactions with barrier function and repair.
|Effective start/end date||9/19/14 → 3/31/19|
- National Institute of Diabetes and Digestive and Kidney Diseases (7K01DK101675)
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