MyD88 and retinoic acid signaling pathways interact to modulate gastrointestinal activities of dendritic cells

Gastroenterology. 2011 Jul;141(1):176-85. doi: 10.1053/j.gastro.2011.04.010. Epub 2011 Apr 16.


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 extraintestinal 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Cells, Cultured
  • Chemotaxis, Leukocyte
  • Coculture Techniques
  • Dendritic Cells / drug effects
  • Dendritic Cells / immunology
  • Dendritic Cells / metabolism*
  • Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Feedback, Physiological
  • Humans
  • Immunoglobulin A, Secretory / metabolism
  • Intestinal Mucosa / metabolism*
  • Intestines / drug effects
  • Intestines / immunology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myeloid Differentiation Factor 88 / deficiency
  • Myeloid Differentiation Factor 88 / genetics
  • Myeloid Differentiation Factor 88 / metabolism*
  • Protein Kinase Inhibitors / pharmacology
  • Signal Transduction* / drug effects
  • T-Lymphocytes, Regulatory / immunology
  • T-Lymphocytes, Regulatory / metabolism
  • Time Factors
  • Toll-Like Receptors / metabolism
  • Tretinoin / administration & dosage
  • Tretinoin / metabolism*


  • Immunoglobulin A, Secretory
  • Myd88 protein, mouse
  • Myeloid Differentiation Factor 88
  • Protein Kinase Inhibitors
  • Toll-Like Receptors
  • Tretinoin
  • Extracellular Signal-Regulated MAP Kinases