W152 - Increased Skeletal Muscle Autophagy Protects from Neutrophil-mediated Gut Inflammation

Abstract Text: Inflammatory bowel disease (IBD), comprising of Crohn’s Disease and Ulcerative Colitis, is a debilitating disease with no known cause. Although extensive work has linked numerous genetic loci to IBD, most of these associations remain incompletely understood. Here, we show that DUPD1/DUSP29, a dual-specificity phosphatase of unknown function, is exclusively expressed in the skeletal muscle, and negatively regulates autophagy in this tissue. As autophagy is a known risk factor in IBD, we tested the role of DUPD1 in colitis. Dupd1-/- mice were protected from dextran sodium sulfate (DSS) and Helicobacter hepaticus induced colitis in Il-10-/- mice, as well as DSS/Azoxymethane (AOM) induced colitis-associated colon cancer (CAC). Deletion of DUPD1 in the skeletal muscle (Dupd1fl/flMyf6Cre) protects mice from colitis. The increased autophagic flux in Dupd1-/- mice was associated with reduced neutrophil-mediated systemic inflammation and reduced neutrophil extracellular traps (NETs) formation in the colonic mucosae, a process known to impair intestinal barrier function and cause mucosal damage. Oral pharmacologic inhibition of DUPD1 catalytic activity led to increased autophagy flux in the skeletal muscle, and reduced colitis in wild type mice. This work shows that the skeletal muscle acts as an immunological organ capable of regulating inflammation at distant sites, and implicates DUPD1 as a potential novel therapeutic target in IBD.