Inflammatory bowel diseases (IBD) are relapsing remitting conditions that manifest as chronic and debilitating inflammation of the intestine in an ever-increasing number of patients in the USA (1). Inappropriate accumulation of CD4 T cells with a Th1 phenotype in the intestinal mucosa plays an indispensable role in maintaining disease pathology (2-8). As such blocking CD4 Th1 T cell trafficking to the inflamed intestine is an area of intense investigation. Recent investigations by the applicant unearthed a surprising role for the neuronal guidance molecule, netrin-1 in blocking leukocyte migration during acute colitis (9). However, the role of netrin-1 in chronic inflammation as observed in IBD is unknown. Excitingly, netrin-1 treatment almost completely reversed histological disease and dramatically decreased the number of effector CD4 T cells in the ileum of mice with Crohn's-like ileitis (TNF?ARE). Following netrin-1 treatment a robust reduction in the expression of Th1 chemokine receptors, CXCR3 and CCR5, was observed in TNF?ARE ileum indicating netrin-1 attenuated a Th1 T cell response. Netrin-1 prevented TNF?ARE CD4 T cell migration towards specific Th1 chemokines in vitro. In vivo homing assays demonstrated netrin-1 blockade of TNF?ARE CD4 T cell trafficking to the inflamed ileum, pointing to a direct effect of netrin-1 on CD4 T cell migration. The applicant identified the intestinal epithelium as the major source of netrin-1 during acute inflammation with netrin-1 mediating an anti- inflammatory response through the A2B adenosine receptor (A2BAR) in acute colitis (9).Interestingly, the A2BAR is expressed to a high level on TNF?ARE CD4 T cells and netrin-1 can induce A2BAR signaling. Adenosine receptor signaling has been implicated in blocking chemokine receptor functional responses, including cell migration (10-12). Based on these findings, we hypothesize that during chronic inflammation intestinal epithelial derived netrin-1 suppresses CD4 Th1 T cell trafficking through an A2B adenosine receptor mediated signaling pathway. A novel genetic model for epithelial specific deletion of netrin-1 will assist in elucidating the functional role of endogenous netrin-1 during development of chronic intestinal inflammation. In vivo and in vitro functional assays will identif the netrin-1 signaling pathway responsible for the therapeutic effect of netrin-1 in TNF?ARE ileitis. The applicant will use the K01 mechanism to develop her knowledge of mucosal immunology and T cell biology by attending focused workshops and conferences. The committee she has assembled to assist her along with her participation in practical courses will educate her in the technology she needs to perform her analyses of CD4 T cell function. The goal of the proposed studies is to use a genetic and pharmacologic approach to determine the role of netrin-1 in chronic intestinal inflammation as occurs in IBD. "
Inflammatory bowel diseases (IBD) are a significant problem affecting greater than 1 million Americans. There is much interest in inhibiting CD4 T cell migration to the intestine due to the importance of these cells in maintaining chronic intestinal inflammation as observed in IBD. Our studies propose that the neuronal guidance molecule netrin-1 is a novel protective mechanism that inhibits CD4 T cell migration to the intestine which may be exploited for future therapeutic benefit in IBD.