title: MyD88 and retinoic acid signaling pathways interact to modulate gastrointestinal activities of dendritic cells.
abstract: OBJECTIVE
  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.
authors: Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.
authors: Eduardo J
authors: EJ
authors: Villablanca
authors: Sen
authors: S
authors: Wang
authors: Jaime
authors: J
authors: de Calisto
authors: Daniel C O
authors: DC
authors: Gomes
authors: Maureen A
authors: MA
authors: Kane
authors: Joseph L
authors: JL
authors: Napoli
authors: William S
authors: WS
authors: Blaner
authors: Hiroyuki
authors: H
authors: Kagechika
authors: Rune
authors: R
authors: Blomhoff
authors: Mario
authors: M
authors: Rosemblatt
authors: Maria Rosa
authors: MR
authors: Bono
authors: Ulrich H
authors: UH
authors: von Andrian
authors: J Rodrigo
authors: JR
authors: Mora
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