Article Text


Inflammatory bowel disease III
PWE-256 Intestinal inflammation regulates retinoic acid dependent imprinting of gut tropism by dendritic cells independently of RALDH expression
  1. T J Sanders1,
  2. N E McCarthy1,
  3. E Giles1,
  4. J O Lindsay2,
  5. A J Stagg1
  1. 1Centre for Immunology and Infectious Disease, Blizard Institute, London, UK
  2. 2Digestive Diseases Clinical Academic Unit, Barts & The London School of Medicine & Dentistry, London, UK


Introduction In the mouse, tissue-specific expression of retinaldehyde dehydrogenase (RALDH) enzymes by CD103+ intestinal dendritic cells (DC) enables them to generate all-trans retinoic acid (RA) and thereby imprint a gut-tropic phenotype on T cells via induction of homing receptors including α4β7 integrin. In health, RA from CD103+ also enhances their generation of Treg, contributing to intestinal homeostasis. In murine models of inflammatory bowel disease (IBD) RALDH expression by CD103+ DC is reduced but little is known about the function of RA in the human intestine. The aim of this study was to determine whether factors present in the healthy and inflamed human intestine regulate RA generation and activity.

Methods Conditioned media (CM) were generated by culture of intestinal biopsies from healthy individuals and IBD patients (inflamed/non-inflamed regions). DC were differentiated from monocytes using GM-CSF and IL-4 in the presence or absence of CM. Expression of RA-generating enzymes was assessed by qRT-PCR and RALDH activity determined using the Aldefluor assay. Induction of α4β7 following activation of naïve allogeneic CD4+ T cells was determined by flow cytometry.

Results Activation of naïve CD4+ T cells by human monocyte-derived DC resulted in RA-dependent upregulation of α4β7. These DC possessed retinal-inhibitable Aldefluor activity and expressed both alcohol dehydrogenase (RDH10) and RALDH (RALDH1,2,3) enzymes required for the generation of RA from retinol via retinal. Aldefluor activity was regulated by GM-CSF and RA, and reflected predominately the activity of RALDH2 as suggested by qRT-PCR analysis of sorted Aldefluor+ DC. CM significantly suppressed Aldefluor activity (p<0.0001) irrespective of whether generated from healthy or IBD tissue (inflamed or non-inflamed). The inhibitory effect of CM generated from healthy tissue could be partially reversed with the prostaglandin E2 (PGE2) EP-2 receptor antagonist AH6809 but this effect was less marked with CM from IBD tissue suggesting the involvement of distinct RALDH regulators. Although the effects of inflamed and non-inflamed CM on Aldefluor activity were similar, DC differentiated in the presence of inflamed CM induced significantly higher (p<0.05) levels of CD4 T cell α4β7 expression.

Conclusion Factors generated in the human intestinal mucosa limit RALDH activity in DC and may thereby impact upon their generation of RA. Factors other than PGE2 are involved particularly in inflamed tissue. Intestinal mediators influence the imprinting of gut tropism independently of effects on RA-generating enzymes. Manipulation of RA availability may offer new therapeutic options in IBD.

Competing interests None declared.

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