Skin-homing receptors on effector leukocytes are differentially sensitive to glyco-metabolic antagonism in allergic contact dermatitis.

Abstract

T cell recruitment into inflamed skin is dependent on skin-homing receptor binding to endothelial (E)- and platelet (P)-selectin. These T cell receptors, or E- and P-selectin ligands, can be targeted by the metabolic fluorosugar inhibitor, 4-F-GlcNAc, to blunt cutaneous inflammation. Compelling new data indicate that, in addition to T cells, NK cells are also recruited to inflamed skin in allergic contact hypersensitivity (CHS) contingent on E- and P-selectin-binding. Using a model of allergic CHS, we evaluated the identity and impact of NK cell E-selectin ligand(s) on inflammatory responses and examined the oral efficacy of 4-F-GlcNAc. We demonstrated that the predominant E-selectin ligands on NK cells are P-selectin glycoprotein ligand-1 and protease-resistant glycolipids. We showed that, unlike the induced E-selectin ligand expression on activated T cells upon exposure to Ag, ligand expression on NK cells was constitutive. CHS responses were significantly lowered by orally administered 4-F-GlcNAc treatment. Although E-selectin ligand on activated T cells was suppressed, ligand expression on NK cells was insensitive to 4-F-GlcNAc treatment. These findings indicate that downregulating effector T cell E- and P-selectin ligand expression directly correlates with anti-inflammatory efficacy and provides new insight on metabolic discrepancies of E-selectin ligand biosynthesis in effector leukocytes in vivo.

• Authors: Madeliene E Gainers, Leyla Descheny, Steven R Barthel, Luzheng Liu, Marc-André Wurbel, Charles J Dimitroff
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 179 Issue 12 Pg. 8509-18 (Dec 15 2007) ISSN: 0022-1767 [Print] United States
• PMID: 18056398 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Homeodomain Proteins
• Membrane Glycoproteins
• P-selectin ligand protein
• Receptors, Fibroblast Growth Factor
• Sialoglycoproteins
• cysteine-rich fibroblast growth factor receptor
• RAG-1 protein
• 2-acetamido-1,3,6-tri-O-acetyl-4-deoxy-4-fluoroglucopyranose
• Acetylglucosamine

Topics

• Acetylglucosamine (administration & dosage, analogs & derivatives)
• Administration, Oral
• Animals
• Dermatitis, Allergic Contact (immunology)
• Homeodomain Proteins (genetics)
• Humans
• Killer Cells, Natural (immunology)
• Membrane Glycoproteins (analysis, antagonists & inhibitors, metabolism)
• Mice
• Mice, Mutant Strains
• Receptors, Fibroblast Growth Factor (analysis, antagonists & inhibitors, metabolism)
• Sialoglycoproteins (analysis, antagonists & inhibitors, metabolism)
• Skin (immunology)
• T-Lymphocytes (immunology)