A188 TARGETING RIPK2 TO TREAT INTESTINAL INFLAMMATION CAUSED BY SHIP DEFICIENCY

Background Crohn’s disease (CD) is a form of inflammatory bowel disease characterized by chronic inflammation along the gastrointestinal tract. We have described the SHIP-/- mouse model of CD-like intestinal inflammation. SHIP-/- mice develop spontaneous ileal inflammation that is characterized by villus hyperplasia and disorganization, edema, immune cell infiltration, ulceration, loss of goblet cells, and muscle wall thickening. SHIP deficiency in people with CD has been associated with a more severe and treatment-refractory disease. Interestingly, NOD2 gene variants, which are the most profound genetic associations for CD, are also associated with a more severe CD phenotype. Muramyl dipeptide (MDP) is a molecular associated microbial pattern, which activates the NOD2 signalling pathway. Recently, SHIP has been reported to play a role in the NOD2 pathway by disrupting the downstream interaction between RIPK2 and XIAP required for NOD2-mediated NFκB activation and pro-inflammatory cytokine production.