Regulation and migratory role of P-selectin ligands during intestinal inflammation

PLoS One. 2013 Apr 22;8(4):e62055. doi: 10.1371/journal.pone.0062055. Print 2013.

Abstract

Dendritic cells from mesenteric lymph nodes (MLN) can convert retinal to retinoic acid (RA), which promotes induction of the gut-specific homing receptor α4β7. In contrast, priming within peripheral lymph nodes leads to upregulation of E- and P-selectin ligands (E- and P-lig). Apart from its α4β7 promoting effect, RA was shown to suppress E- and P-lig induction in vitro. However, enhanced frequencies of P-lig(+) CD4(+) T cells were reported during intestinal inflammation. To understand this contradiction, we first determined whether location of intestinal inflammation, that is, ileitis or colitis, affects P-lig induction. Both conditions promoted P-lig expression on CD4(+) T cells; however, P-lig expressed on T cells facilitated Th1 cell recruitment only into the inflamed colon but not into inflamed small intestine induced by oral Toxoplasma gondii infection. A majority of P-lig(+)CD4(+) T cells found within MLN during intestinal inflammation co-expressed α4β7 confirming their activation in the presence of RA. Mesenteric P-lig(+)CD4(+) cells co-expressed the 130 kDa isoform of CD43 which requires activity of core 2 (beta)1,6-N-acetyl-glycosaminyltransferase-I (C2GlcNAcT-I) suggesting that C2GlcNAcT-I contributes to P-lig expression under these conditions. To test whether inflammatory mediators can indeed overrule the inhibitory effect of RA on P-lig expression we stimulated CD4(+) T cells either polyclonal in the presence of IL-12 and IFNγ or by LPS-activated MLN-derived dendritic cells. Both conditions promoted P-lig induction even in the presence of RA. While RA impeded the induction of fucosyltransferase-VII it did not affect IL-12-dependent C2GlcNAcT-I induction suggesting that C2GlcNAcT-I can support P-lig expression even if fucosyltransferase-VII mRNA upregulation is dampened.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / metabolism
  • Cell Movement
  • Colitis / immunology*
  • Colitis / metabolism
  • Colitis / pathology
  • Dendritic Cells / immunology
  • Dendritic Cells / metabolism
  • Female
  • Gastroenteritis / immunology
  • Gastroenteritis / metabolism
  • Gastroenteritis / pathology
  • Integrins / metabolism
  • Intestine, Small / immunology*
  • Intestine, Small / metabolism
  • Intestine, Small / pathology
  • Lipopolysaccharides / pharmacology
  • Membrane Glycoproteins / physiology*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, SCID
  • Th1 Cells / physiology
  • Tretinoin / physiology

Substances

  • Integrins
  • Lipopolysaccharides
  • Membrane Glycoproteins
  • P-selectin ligand protein
  • integrin alpha4beta7
  • Tretinoin

Grants and funding

This work was supported by the Deutsche Forschungsgemeinschaft (TR 52, SFB 633) and BMBF (CIPP). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.