Journal
GASTROENTEROLOGY
Volume 141, Issue 1, Pages 176-185Publisher
W B SAUNDERS CO-ELSEVIER INC
DOI: 10.1053/j.gastro.2011.04.010
Keywords
Inflammation; IBD; Immune Response; Mouse Model
Categories
Funding
- Crohn's & Colitis Foundation of America
- Fondecyt [1100557, 1100448]
- Conicyt [PFB16]
- National Institutes of Health [DP2 2009A054301]
- Cancer Research Institute
- Massachusetts Life Science Center
- Grants-in-Aid for Scientific Research [22136013] Funding Source: KAKEN
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BACKGROUND & AIMS: Gut-associated dendritic cells (DC) metabolize vitamin A into all-trans retinoic acid (RA), which is required to induce lymphocytes to localize to the gastrointestinal tract and promotes the differentiation of Foxp3(+) regulatory T cells and IgA antibody-secreting cells. We investigated whether RA functions in a positive-feedback loop in DC to induce its own synthesis. METHODS: We measured levels of retinoids in intestinal tissues from mice and assessed the role of RA in the functional specialization of gut-associated DC in cell cultures and mice. We used pharmacologic antagonists to determine the signaling pathways involved in regulation of DC and used MyD88(-/-) mice to determine the contribution of Toll-like receptor signaling in RA-mediated effects on DC. RESULTS: The concentration of retinoids decreased in a proximal-to-distal gradient along the intestine, which correlated with the activity of gut-specific DC. Importantly, RA regulated the ability of gut-associated DC to produce RA, induce T cells to localize to the gastrointestinal tract, and generate regulatory T cells and IgA-secreting cells. RA was sufficient to induce its own production by extra-intestinal DC in vitro and in vivo. RA-mediated regulation of DC required signaling through the mitogen-activated protein kinase signaling pathway and unexpectedly required MyD88, which is conventionally associated with Toll-like receptor, interleukin-1, and interleukin-18 signaling. CONCLUSIONS: RA is necessary and sufficient to induce DC to regulate T-cell localization to the gastrointestinal tract and IgA secretion. Our findings also indicate crosstalk between the RA receptor and MyD88-dependent Toll-like receptor signaling pathways.
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