Inflammatory Bowel Disease (IBD) currently affects 1 to 2 million individuals with the peak onset occurring between 15 and 25 years of age. It is thought to occur in genetically susceptible hosts due to a dysregulated T cell mucosal immune response to commensal enteric bacteria. There is evidence that IBD is a Th1 mediated attack (Crohn's), while cytokine changes consistent with a Th2-type response have been described (ulcerative colitis) with considerable overlap existing. Recently, Th17 pathways have been implicated as critical to IBD, further clouding the relative roles these effector pathways play in IBD. Understanding homing mechanisms that determine how these effector responses are translated from peripheral priming to extralymphoid effector sites (intestine) is critical to understanding the pathogenesis of IBD and may provide therapeutic targets. Data have demonstrated the homing ligand P-selectin glycoprotein (PSGL)1 is upregulated on Th1 cells, its receptor, P-selectin, is constitutively expressed on intestinal endothelial cells, and its expression is upregulated in states of inflammation. Studies have shown its requirement for the development of spontaneous murine ileitis, as well as established murine colitis. It has been shown to participate in regulatory function through homing of T regulatory cells and polarizing properties of dendritic cells. In studies for this proposal, PSGL1 was required for the recruitment of Th1 cells to an acutely inflamed colon (recruitment decreased 81%), and deletion of PSGL1 attenuated acute DSS colitis. However, deletion of PSGL1 in IL10-/- mice resulted in increased disease severity, increased influx of macrophages and CD4+ cells, suggesting a complicated, multifactorial role for PSGL1 in this model. Based on this data, we propose PSGL1 is critical for Th1 recruitment in colitis, but that its role in overall T cell recruitment (e.g. Th17, T regulatory) is unclear, as well as its role in dendritic cell and macrophage recruitment/function. In studies proposed here, the biologic significance of PSGL1 will be further investigated in IL10-/- colitis. We hypothesize PSGL1 plays a complex role coordinating effector as well as regulatory responses in colitis. The long term objective of this proposal is to generate data that will elucidate pathogenic mechanisms in IBD, providing the background to ask more mechanistic questions in a future RO1 proposal, acting as a vehicle to transition to an independent investigator. We propose to focus on the following specific aims: 1)Examine the relative contribution of PSGL1 to the recruitment of independent CD4+ T-helper subsets and the development of colitis by a)Determine the requirement for PSGL1 in the accumulation of effector CD4+ cells in the IL10-/- to RAG1-/- transfer model of colitis, b) Examine whether the absence or presence of Th1 responses result in regulation of Th17 function in this model, and c) Examine the role of PSGL1 in IL10-/- CD4+ has on macrophage function;2) Determine the requirement for PSGL1 in the accumulation of macrophages in the IL10-/- to RAG1-/- transfer model of colitis by determining the requirement for (a) recipient PSGL1 vs. (b) transferred PSGL1 in the accumulation of macrophages in the IL10-/- to RAG1-/- transfer model of colitis.
Inflammatory bowel disease affects 1-2 million individuals and is thought to result from a poorly regulated immune response (leukocytes) to normal intestinal bacteria. Unfortunately, current therapies (e.g. steroids) are often unsuccessful and carry their own significant morbidities. Investigating pathways like PSGL-1 may elucidate pathologic mechanisms defining how these leukocytes traffic to the intestine and provide new therapeutic targets.
