7th Annual BMRP Investigator Meeting - Abstract

 

 

The secreted c-type lectin PAP/REG3b is critically involved in the acute-phase resolution of inflammation in the liver and the pancreas and is over-expressed upon tissue injury, such as in inflammatory bowel diseases (IBD). Here, we describe a new regulatory function for PAP/REG3b in the gut-microbiota dialogue. Our data revealed that the Crohn’s disease-associated NOD2 mutations are linked to increased serum PAP/REG3b levels, suggesting that the latter might play a role in IBD pathogenesis. To formally decipher the physiological role of PAP/REG3b in the colon, we used a transgenic mouse model of PAP/REG3b deficiency. Bacteriological analysis revealed that the steady-state composition of the microbiota of Reg3b-deficient animals was markedly changed when compared to wild-type animals, with a shift in the abundance of the Escherichia coli and the lactobacilli. Unexpectedly, induction of colonic injury by dextran sodium sulfate resulted in significantly less intestinal damage in Reg3b-deficient mice than in their wild-type littermates, as measured by associated mortality, clinical/histological scores and myeloperoxidase activity in the colon. Administration of exogenous recombinant PAP/REG3b triggered macrophages activation and polymorphonuclear neutrophil influx in vivo. Consistently, PAP/REG3b is required for optimal expression of the resistin-like molecule b, which is involved in the Th2-mediated mucosal inflammatory response and was found to be over-secreted by the colonic mucosa of IBD patients. It is concluded that PAP/REG3b is an essential intestinal regulator of both the composition of the fecal microbiota and of the intricate control of neutrophil-associated tissue damage in the colon.