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

• Published in: PloS one 2013-04, Vol.8 (4), p.e62055-e62055
• Main Authors: Hoffmann, Ute, Pink, Matthias, Lauer, Uta, Heimesaat, Markus M, Winsauer, Caroline, Kruglov, Andrei, Schlawe, Kerstin, Leichsenring, Claudia, Liesenfeld, Oliver, Hamann, Alf, Syrbe, Uta
• Format: Article
• Language: English
• Subjects: Animals; Antigens; Biology; CD4 antigen; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; CD43 antigen; Cell migration; Cell Movement; Colitis; Colitis - immunology; Colitis - metabolism; Colitis - pathology; Colon; Dendritic cells; Dendritic Cells - immunology; Dendritic Cells - metabolism; Female; Gastroenteritis - immunology; Gastroenteritis - metabolism; Gastroenteritis - pathology; Gene expression; Homing; Ileitis; Inflammation; Inflammatory bowel disease; Integrins - metabolism; Interleukin 12; Intestine, Small - immunology; Intestine, Small - metabolism; Intestine, Small - pathology; Ligands; Lipopolysaccharides; Lipopolysaccharides - pharmacology; Lymph nodes; Lymphatic system; Lymphocytes; Lymphocytes T; Medicine; Membrane Glycoproteins - physiology; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, SCID; mRNA; P-selectin; Priming; Recruitment; Retina; Retinoic acid; RNA; Rodents; Skin; Small intestine; T cells; Th1 Cells - physiology; Toxoplasma gondii; Tretinoin - physiology; γ-Interferon
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0062055

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.