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Skin-Homing Receptors on Effector Leukocytes Are Differentially Sensitive to Glyco-Metabolic Antagonism in Allergic Contact Dermatitis¹

Harvard Skin Disease Research Center, Department of Dermatology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115

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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by an American Cancer Society Grant RSG-06–024-01-CSM (to C.J.D.), National Institutes of Health/National Cancer Institute Grants CA102913 (to C.J.D.) and CA118124 (to C.J.D.), and National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases Grant 5P30 AR042689–14 (to T.S.K.).

² Address correspondence and reprint requests to Dr. Charles J. Dimitroff, Harvard Institutes of Medicine, Room 650, 77 Avenue Louis Pasteur, Boston, MA 02115. E-mail address: cdimitroff{at}rics.bwh.harvard.edu

³ Abbreviations used in this paper: CHS, contact hypersensitivity; P, platelet; E, endothelial; L, leukocyte; PSGL-1, P-selectin glycoprotein ligand-1; wt, wild type; p.o., orally; LN, lymph nodes; DNFB, 2,4-dinitrofluorobenzene; ILN, inguinal LN; ESL-1, E-selectin ligand-1.

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