Innate immune activation of macrophages during Colitis. (360G-Wellcome-087837_Z_08_Z)

Ulcerative colitis arises from breakdown of the dynamic balance between intestinal microflora and the host immune response. The importance of pathogenic and regulatory subsets of T cells in colitis is well established. However, no systematic study has been carried out to investigate the direct involvement of macrophages in intestinal inflammation. Previously, I have defined a novel innate activation of macrophages arising from direct microbial stimulation of pattern recognition receptors. Simila r direct activation also occurs during lymphocyte dependent and independent models of colitis, indicating that innate activation of macrophages is possibly the primary cause of inflammatory bowel disease. Using a newly developed spontaneous model of colitis arising from selective loss of alpha v integrin on myeloid cells, I will test whether such direct activation of macrophages itself is sufficient to induce colitis. I will further establish- 1) how myeloid expressing alpha v regulates excessi ve macrophage activation and prevent colitis, 2) whether regulatory subset of lymphocytes can control excessive macrophages activation and prevent colitis. I will answer these questions by developing powerful genetic techniques and dissecting myeloid specific gene functions. This project will confirm a central role of innate-activated macrophages in the development of colitis.