Tu1852 Resveratrol Ameliorates Oxidative Stress-Induced Intestinal Epithelial Barrier Dysfunction by Upregulating Heme Oxygenase-1 Expression

Crohn's disease (CD) is a chronic, relapsing inflammatory disease, which affects nearly 1.4 million Americans. Genome-wide association studies (GWAS) have identified several genetic risk loci for CD including IRGM (immunity-related GTPase family M). IRGM functions in the innate immune control of intracellular pathogens. IRGM localizes to the mitochondria and induces mitochondrial fission which is linked to the autophagic elimination of intracellular bacteria. Surprisingly, IRGM expression is not lost but stronger in the epithelium of CD patients carrying the IRGM risk allele and more unexpectedly it is associated with an increase in intracellular bacteria. So how IRGM signaling contributes to the pathogenesis of CD remains unresolved. Our laboratory has generated a unique mouse model (DKO) of CD with a high mucosal expression of IRGM which duplicates the functional, histological and clinical features of human CD. The DKO mice were generated by genetic deletion of two anti-apoptotic proteins (villin/gelsolin) that regulate mitochondrial homeostasis and mucosal healing. Our studies with DKO mice and human CD patients demonstrate that by acting on the mitochondria, IRGM confers autophagic protection when expressed in moderation but induces cell death when over-expressed, explaining IRGM's action both in defense against bacteria and in damaging inflammation in CD. Furthermore, IRGM induced cell death is accompanied by the release of HMGB1 (high mobility group protein B1), a major proinflammatory alarmin/DAMP (danger-associated molecular pattern). This we demonstrate is the molecular basis of IRGM's role in the pathogenesis of CD. Our innovative study uses a novel mouse model of CD, provides a novel paradigm about the role of IRGM in CD and includes translational studies to diagnose, treat and monitor CD patients.