Skin-homing receptors on effector leukocytes are differentially sensitive to glyco-metabolic antagonism in allergic contact dermatitis.
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.
Harvard Skin Disease Research Center, Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Madeliene E
ME
Gainers
Leyla
L
Descheny
Steven R
SR
Barthel
Luzheng
L
Liu
Marc-André
MA
Wurbel
Charles J
CJ
Dimitroff
D000117:Acetylglucosamine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D000284:Administration, Oral; D000818:Animals; D017449:Dermatitis, Allergic Contact / Q000276:immunology*; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D017468:Receptors, Fibroblast Growth Factor / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012795:Sialoglycoproteins / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012867:Skin / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*
D018398:Homeodomain Proteins; D008562:Membrane Glycoproteins; C084882:P-selectin ligand protein; D017468:Receptors, Fibroblast Growth Factor; D012795:Sialoglycoproteins; C086711:cysteine-rich fibroblast growth factor receptor; C064658:RAG-1 protein; C089178:2-acetamido-1,3,6-tri-O-acetyl-4-deoxy-4-fluoroglucopyranose; D000117:Acetylglucosamine