Trail in Regulation of Gut Inflammation and Mucosa Immunity

Members of the tumor necrosis factor superfamily (TNFSF) are molecules of broad spectrum of activity, including apoptosis, direct disruption of intestinal epithelial barrier integrity and costimulation of proinflammatory functions of lymphocytes. Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) has been implicated in the regulation of inflammation in autoimmune diseases. TRAIL has long been regarded as a proapoptotic signal transducer, and most of its regulatory role was believed mainly due to promoting cell apoptosis in synoviocytes and/or infiltrating lymphocytes. Recent accumulating evidence suggests that TRAIL may have an apopt os is-independent role in immune regulation. In addition to triggering apoptosis, TRAIL itself can directly inhibit T cell activation via interaction with the TRAIL receptor. In our team's studies with Professor Hsu in NTU, we have demonstrated that TRAIL significantly inhibited joint inflammation and reduced the severity of arthritis in inflammatory arthritis animal model. Suppression of joint inflammation was not due to inducing apoptosis in T cells, macrophages, or synovial fibroblasts by TRAIL. In contrast, TRAIL directly inhibited T cell proliferation, indicating that TRAIL exerted its anti-inflammatory effects directly through inhibition of T cell activation (Cell Mol Immunol 2016, in press). All these results suggest an apoptosis-independent role of TRAIL in the immune system and raise potential therapeutic implications of TRAIL in inflammatory autoimmune diseases. However, role of TRAIL in inflammatory bowel disease (IBD) is not clear. Immune cells, mucosal epithelia, and intestinal microbiota all contribute to the pathogenesis of inflammatory bowel diseases. The aim of this study was to investigate the immunomodulatory mechanism and role of TRAIL in inflammatory bowel disease. In our preliminary results, we have demonstrated that TRAIL reduced colonic inflammation and disease severity in DSS colitis model. Moreover, TRAIL-receptor (TRAIL-R) knockout mice developed more severe disease, and the protective effects of TRAIL were abolished in TRAIL-R knockout mice in the DSS colitis model. In this project, we further explore the role and mechanism of TRAIL in IBD and mucosa immunity. First. we will study role of TRAIL in IBD via different animal models to confirm its therapeutic potential in human IBD. Second, we will study the target immune effector cells by TRAIL, in particular, the direct effects on T cells, and the role of TRAIL in inhibiting T cell activation, or induction of Treg cells in the colon during gut inflammation. This will be further addressed by adoptive transfer of TRAIL treated WT or TRAIL-R KO T cells in the T cell transfer colitis model. The effects on induction of Terg cells by TRAIL will be further investigated by using Foxp3-GFP knockin mice. Finally, the effects of TRAIL on T cell activation and mucosa immunity will be analysed by gene array and RNA sequenc ing to ide ntify the candidate TRAIL targeted genes. This study will further refine our knowledge regarding TRAIL in T cell activation and mucosal immunity, and also sheds light on the development of effective therapy in treatment of human autoimmune diseases.