Targeting inhibitors of NOD2 signaling to allow productive inflammation in genetic inflammatory disease (157.9)

Abstract

Abstract The intracellular bacterial sensor, NOD2, coordinates innate immune signaling pathways. Maintaining appropriate activation of NOD2 is paramount in immunologic homeostasis as dysregulation of NOD2 signaling causes a variety of inflammatory diseases including Crohn’s disease (CD). We have identified the atypical TRAF family member, TRAF4, as a key inhibitor of NOD2 signaling. We show that this inhibition occurs through two mechanisms - through IKK phosphorylation and activation of TRAF4 and through direct binding of TRAF4 to NOD2. Further work shows that TRAF4 also binds CD-associated NOD2 variants and we hypothesize that competing TRAF4 from these NOD2 variants could allow a productive inflammatory response. To this end, we have generated cell permeable peptides that mimic the region of NOD2 that binds TRAF4 in hopes of competing TRAF4 from NOD2 in vitro and in vivo to prevent the inhibitory effect of TRAF4. This may partially revert loss-of-function CD-associated NOD2 variants and could serve as a platform for future therapeutics in Crohn’s disease patients harboring these mutations.