Exocytosis of MUC2 is Regulated by VAMP8 and Plays a Critical Role in DSS-Induced Colitis

The gastrointestinal mucus layers provide the first line of innate host defense by spatially separating potential threats and pathogens away from the surface epithelium. Goblet cells produce, store and secrete MUC2 mucin constitutively and in response to noxious substances and pathogens by an unknown mechanism.  In this study, we characterized the exocytosis machinery that is responsible for the release of MUC2 as SNAP23, Syntaxin 3, VAMP8 and Munc18b by pull-down and confocal microscopy.  Mucin exocytosis was driven by both calcium and PKCδ through independent mechanisms. Knock down of SNAP23 and VAMP8 by shRNA in colonic goblet cells significantly decreased both constitutive and induced MUC2 exocytosis. In Vamp8^-/- mice the colonic epithelium showed gross structural deformities in crypt architecture, goblet cell hypertrophy, enlarged granules and surface epithelium erosion as compared to Vamp8^+/- and Vamp^+/+ littermates. Vamp8^-/- mice were highly susceptible to DSS-induced colitis and all animals succumb to disease by day 6. This coincided with higher disease activity index scores with increased neutrophil infiltrate and MPO levels. These results demonstrate that the MUC2 exocytosis machinery is highly regulated and highlight the importance of the mucus barrier in normal and disease states.