Journal
JOURNAL OF IMMUNOLOGY
Volume 179, Issue 12, Pages 8509-8518Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.179.12.8509
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Funding
- NCCIH NIH HHS [R01 AT004628] Funding Source: Medline
- NCI NIH HHS [R01 CA118124, CA102913, CA118124, R21 CA104828, R21 CA102913] Funding Source: Medline
- NIAMS NIH HHS [5P30 AR042689-14, P30 AR042689-150049, P30 AR042689] Funding Source: Medline
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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-GlcNAe, 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.
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