MyD88 and Retinoic Acid Signaling Pathways Interact to Modulate Gastrointestinal Activities of Dendritic Cells
Published Date:Apr 16 2011
Source:Gastroenterology. 2011; 141(1):176-185.
Keywords:Analysis Of Variance
Extracellular Signal-Regulated MAP Kinases
Immunoglobulin A, Secretory
Mice, Inbred C57BL
Myeloid Differentiation Factor 88
Protein Kinase Inhibitors
Pubmed Central ID:PMC3129445
Funding:DP2 2009A054301/DP/NCCDPHP CDC HHS/United States
DP2 OD006512-01/OD/NIH HHS/United States
P30 AI060354/AI/NIAID NIH HHS/United States
R01 AA017927/AA/NIAAA NIH HHS/United States
R01 AI069259/AI/NIAID NIH HHS/United States
R01 DK090522/DK/NIDDK NIH HHS/United States
Description: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 (GI) tract and promotes the differentiation of Foxp3+ regulatory T cells (TREG) and immunoglobulin (Ig)A antibody-secreting cells (IgA-ASC). We investigated whether RA functions in a positive-feedback loop, via DC, to induce its own synthesis.
We measured levels of retinoids in intestine tissues from mice and assessed the role of RA in activities 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 (TLR) signaling in RA-mediated activities of DC.
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 GI tract, and generate TREG 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 has been associated with TLR, interleukin (IL)-1, and IL-18 signaling.
RA is necessary and sufficient to induce DC to regulate T-cell localization to the GI tract and IgA secretion. These findings indicate crosstalk between the RA receptor and MyD88-dependent TLR signaling pathways.
application/pdf application/octet-stream image/gif image/jpeg image/gif image/jpeg image/gif image/jpeg image/gif image/jpeg image/gif image/jpeg image/gif image/jpeg image/gif image/jpeg
You May Also Like: