18 MYELOID VITAMIN D RECEPTOR SIGNALING REGULATES PANETH CELL FUNCTION AND INTESTINAL HOMEOSTASIS. (18th January 2018) - Bakke, Danika
Abstract: Background: Vitamin D receptor (VDR) regulates the biological actions of the active vitamin D metabolite, 1α, 25-dihydroxyvitamin D3. Evidence strongly supports that VDR signaling is involved in the genetic, environmental, immune, and microbial aspects of inflammatory bowel diseases (IBD). Low VDR expression and dysfunction of vitamin D/VDR signaling are reported in patients with both Crohn's disease and ulcerative colitis. Knockout of ATG16L1, a VDR target gene and an IBD risk gene, in myeloid cells promotes dysbiosis. However, the mechanism of myeloid VDR signaling in microbiota regulation and intestinal homeostasis has not been fully elucidated. We hypothesize that myeloid VDR signaling is critical in intestinal homeostasis and probiotics protect macrophages from bacterial infection in a VDR-dependent manner. Methods: We use myeloid-specific VDR knockout (VDRΔLyz) and VDR-/- mouse lines to determine the significance of myeloid VDR signaling in colitis. Results: The VDRΔLyz mice exhibit reduced LC3II expression in the small intestine, suggesting diminished autophagy. They also exhibit altered Paneth cell morphology and spatial distribution, suggesting myeloid immune cells regulate Paneth cells in a VDR-dependent mechanism. We have found that VDR mediates the protective effects of probiotics against Salmonella-colitis in mice. In vitro, our data suggests that microbial proteins from the probiotic Lactobacillus paracasei DKL121-conditioned media enhances VDR expression and reverses the anti-apoptotic effect of Salmonella Typhimurium infection. Overall, loss of myeloid VDR signaling causes Paneth cell dysfunction, allowing for increased bacterial invasion, and renders macrophages less able to defend against the pathogens. Conclusion: Myeloid VDR signaling is critical in maintaining host health. Our study provides new insight into the importance of myeloid VDR signaling to prevent dysbiosis and to attenuate intestinal inflammation.