Intestinal Inflammation: Signaling proteins and the rate of PMN transmigration

Abstract Recent reports by our group and others have highlighted the beneficial and detrimental nature of innate immune cell interactions with intestinal epithelia. Indeed, as observed in Inflammatory Bowel Disease (IBD), an excessive inflammatory response not only results in mucosal injury but is also detrimental for wound repair. We are now beginning to appreciate that intestinal wound repair is regulated, in part, by common receptors expressed on both leukocytes and intestinal epithelial cells (IECs). We recently determined that the ubiquitously expressed membrane protein CD47 is necessary for regulating mucosal wound healing in the intestine and our current data indicates a role for CD47 in both neutrophil (PMN) recruitment and IEC migration. Our preliminary data suggests that CD47-deficient IECs and PMN express less thrombospondin-1 (TSP1), a soluble ligand for CD47, which promotes PMN recruitment to injured mucosa. PMNs, as the first responders, also secrete Leukotriene B4 (LTB4) that binds to its high affinity receptor BLT1 expressed on PMN and amplifies their recruitment. Interestingly, we recently found that IECs also express BLT1 and its ligation by LTB4 promotes mucosal wound repair. In this project, LTB4 and TSP1 are separately evaluated as ligands for receptors expressed on PMNs and IECs during inflammation and repair in the gut. We will build on our preliminary data and previous studies to move toward our goal of understanding mechanisms regulating mucosal wound repair under inflammatory conditions as seen in IBD. These studies will not only shed new light on the complex interplay between inflammatory cells and epithelial cells in orchestrating intestinal mucosal injury/repair in health and disease but may provide new ideas for druggable targets to promote wound repair during mucosal inflammation.