Resident intestinal dendritic cells - negative regulators of colitis

A. Overall Objectives. Resident DCs play important roles in preventing inflammatory responses in the intestinal tract, in part by promoting development of more Tregs. We have shown that deletion of resident DCs increases susceptibility to DSS colitis [1, 2], demonstrating a protective role for resident intDCs. Functional plasticity by DCs raises the possibility that these cells can be made anti-inflammatory. However, understanding mechanisms regulating immunosuppressive functions of intDCs is critical. We show that PPARã has an important role in maintaining an immunosuppressive and tolerogenic phenotype in mouse intDCs. Using a novel conditional deletion mouse strain developed in our lab, we will test the hypothesis that PPARã functions as a master regulator of immune function in intDCs and that reduced expression and/or function of PPARã in DCs increases susceptibility to colitis. We will determine if similar changes in PPARã occur in intDCs from patients with IBD and whether DCs from IBD patients maintain responsiveness to activated PPARã. Finally, we will delineate molecular changes in PPARã protein that occur in intDCs during colitis. Understanding how PPARã levels and activity are altered in intDCs during colitis may lead to novel targeted therapeutic approaches for IBD.