Increased production of retinoic acid by intestinal macrophages contributes to their inflammatory phenotype in patients with crohn's disease

Theodore J. Sanders, Neil E. McCarthy, Edward M. Giles, Katherine L M Davidson, Myriam L R Haltalli, Sophie Hazell, James O. Lindsay, Andrew J. Stagg

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56 Citations (Scopus)

Abstract

Background & Aims Reduced generation of all-trans retinoic acid (RA) by CD103+ intestinal dendritic cells (DCs) is linked to intestinal inflammation in mice. However, the role of RA in intestinal inflammation in humans is unclear. We investigated which antigen-presenting cells (APCs) produce RA in the human intestine and whether generation of RA is reduced in patients with Crohn's disease (CD). Methods Ileal and colonic tissues were collected from patients with CD during endoscopy or surgery, and healthy tissues were collected from subjects who were undergoing follow-up because of rectal bleeding, altered bowel habits, or cancer (controls). Cells were isolated from the tissue samples, and APCs were isolated by flow cytometry. Retinaldehyde dehydrogenase (RALDH) activity was assessed by Aldefluor assay, and ALDH1A expression was measured by quantitative real-time polymerase chain reaction. Macrophages were derived by incubation of human blood monocytes with granulocyte-macrophage colony-stimulating factor (GM-CSF). Results CD103 + and CD103- DCs and CD14+ macrophages from healthy human intestine had RALDH activity. Although ALDH1A1 was not expressed by DCs, it was the predominant RALDH enzyme isoform expressed by intestinal CD14+ macrophages and their putative precursors, CD14+ monocytes. RALDH activity was up-regulated in all 3 populations of APCs from patients with CD; in CD14+ macrophages, it was associated with local induction of ALDH1A1 expression. Blocking of RA receptor signaling during GM-CSF-mediated differentiation of monocytes into macrophages down-regulated CD14 and HLA-DR expression and reduced the development of tumor necrosis factor α-producing inflammatory macrophages. Conclusions RA receptor signaling promotes differentiation of human tumor necrosis factor α-producing inflammatory macrophages in vitro. In vivo, more CD14+ macrophages from the intestinal mucosa of patients with CD than from controls are capable of generating RA, which might increase the inflammatory phenotype of these cells. Strategies to reduce the generation of RA by CD14+ macrophages could provide new therapeutic options for patients with CD.

Original languageEnglish
Pages (from-to)1278-1288.e2
Number of pages13
JournalGastroenterology
Volume146
Issue number5
DOIs
Publication statusPublished - 2014
Externally publishedYes

Keywords

  • Cytokine
  • Immune Response
  • Inflammatory Bowel Disease
  • Keywords
  • Regulation

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