Impact of CD83 on the maintenance of intestinal metabolic and immune homeostasis

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The gut microbiota mediates colonization resistance against intestinal pathogens and affects the availability of anti-inflammatory mediators. Thus, disrupted microbiota and subsequent altered availability of immune and metabolic active molecules are frequently associated with infection-mediated colitis or inflammatory bowel disease (IBD). The pathways engaged by the microbiota, however, and their mutual interaction(s) with the host have not been completely uncovered so far. CD83, a member of the immunoglobulin receptor super-family, affects immune responses and microbial survival locally when expressed on myeloid or epithelial cells and via long distances when released in its soluble form. Interestingly, only certain bacteria elicit the release of soluble CD83 (sCD83) by DCs . To understand the cell-specific biology of CD83, we generated conditional CD83-/- (cCD83-/-) mice. While a reduced bacterial replication and translocation correlated with the induction of a mild colitis during acute Salmonella infection of DC-specific cCD83-/- animals, chronic infection promoted inflammation and altered glycolysis in DCs. Thus, these data strongly suggest that a DC-specific CD83 deletion perpetuates the clearance of acute bacterial infections, but impairs the resolution of chronic inflammation. Intestinal epithelial cell-specific cCD83-/- mice, in contrast, succumbed to infections with gastrointestinal pathogens. Thus, we hypothesize that CD83 modulates intestinal inflammation, metabolism and microbial survival in a cell-specific manner. To uncover the pathogenic mechanisms underlying these phenotypes, we aim to (i) explore the impact of microbes and inflammation on CD83 expression, (ii) define the CD83-expressing cell subsets crucial for bacterial clearance and the resolution of inflammation, (iii) determine the effect(s) of CD83 on the composition and distribution of intestinal microbiota, (iv) characterize the microenvironmental and metabolic products affecting expression and release of CD83 and downstream signaling pathways in mice; and (v) translate our findings obtained in preclinical models into human disease by analysing patient samples for CD83 expression and release. The characterization of the immunemodulating CD83 molecule and the analysis of the molecular mechanisms following CD83 activation during microbe-driven mucosal inflammation might not only contribute to an improved understanding of the pathogenesis of IBD and infectious colitis, but might also allow the development of novel therapeutic strategies that are urgently needed for the treatment of these widespread and devastating diseases.