Grant: Operating Grant

Development of inflammatory bowel diseases (IBDs) is the result of multiple factors, including inappropriate immune responses to normal gut bacteria, and disruption of the intestinal epithelium (the barrier between gut and surrounding tissues) leading to bacterial escape. Distinct populations of immune cells govern the nature/magnitude of protective immunity in the gut. Recent studies suggest that previously unrecognized populations of cells called innate lymphoid cells (ILCs) might be important in dampening the immune responses leading to IBD. However, researchers currently have a rudimentary understanding of the physiological roles of ILCs in intestinal health/disease. Understanding how ILCs contribute to inflammation in the gut promises to uncover new and exciting approaches toward controlling IBD. We recently discovered that a protein present in immune cells, called Lyn, is key in indirectly activating ILCs (through dendritic cells (DCs), inducing them to secrete a protective factor IL-22. We also discovered that Lyn increases barrier function during gut inflammation. Using sophisticated mouse models, we showed that loss of Lyn led to an increase in the development of colitis (a form of intestinal inflammation) while enhancing Lyn-dependent signals in the immune system was protective against colitis. Here we propose to use Lyn loss-and gain-of function approaches together with mouse intestinal inflammatory disease models to determine the biochemical mechanisms underlying the control of DCs and/or ILCs by Lyn, elucidate the roles played by the different subsets of ILCs, and understand how Lyn controls barrier integrity, thereby better understanding how Lyn regulates IBD.