Prevention of leukocyte migration to inflamed skin with a novel fluorosugar modifier of cutaneous lymphocyte-associated antigen
Charles J. Dimitroff, … , Thomas S. Kupper, Robert Sackstein
Charles J. Dimitroff, … , Thomas S. Kupper, Robert Sackstein
Published October 1, 2003
Citation Information: J Clin Invest. 2003;112(7):1008-1018. https://doi.org/10.1172/JCI19220.
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Article Dermatology

Prevention of leukocyte migration to inflamed skin with a novel fluorosugar modifier of cutaneous lymphocyte-associated antigen

Abstract

E-selectin and P-selectin on dermal postcapillary venules play critical roles in the migration of effector T cells into inflamed skin. P-selectin glycoprotein ligand-1 (PSGL-1) modified by α1,3-fucosyltransferase is the principal selectin ligand on skin-homing T cells and is required for effector T cell entry into inflamed skin. We have previously shown that a fluorinated analog of N-acetylglucosamine peracetylated-4-fluorinated-D-glucosamine (4-F-GlcNAc), inhibits selectin ligand expression on human T cell PSGL-1. To analyze 4-F-GlcNAc efficacy in dampening effector T cell migration to inflamed skin, we elicited allergic contact hypersensitivity (CHS) reactions in mice treated with 4-F-GlcNAc. We also investigated 4-F-GlcNAc efficacy on lymphocyte E-selectin ligand expression in LNs draining antigen-sensitized skin and on other immunological processes requisite for CHS responses. Our results showed that 4-F-GlcNAc treatment attenuated lymphocyte E-selectin ligand expression in skin-draining LNs and prevented CHS reactions. Significant reductions in inflammatory lymphocytic infiltrate were observed, while pathways related to antigenic processing and presentation and naive T cell recognition within skin-draining LNs were unaffected. These data indicate that 4-F-GlcNAc prevents CHS by inhibiting selectin ligand activity and the capacity of effector T cells to enter antigen-challenged skin without affecting the afferent phase of CHS.

Authors

Charles J. Dimitroff, Thomas S. Kupper, Robert Sackstein

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Parallel-plate flow chamber analysis of E- and P-selectin binding of mur...
Parallel-plate flow chamber analysis of E- and P-selectin binding of murine Th cells following 4-F-GlcNAc treatment. Murine Th1 cells were generated from spleens of C57BL/6 wild-type and FucTVII-deficient mice. To assess the effects of 4-F-GlcNAc on the de novo synthesis of selectin ligands, Th1 cell cultures were first treated with neuraminidase (0.1 U/ml for 1 hour at 37°C) and then regrown for 30 hours in fresh medium containing PBS (diluent), 0.05 mM 4-F-GlcNAc, 0.23 mM swainsonine, or 1 mM GlcNAc (negative control). Cells were harvested, suspended in HBSS with 2 mM CaCl2 and 10 mM HEPES, and perfused over human recombinant E-selectin–Ig chimera (a) or P-selectin–Ig chimera (b) in the parallel-plate flow chamber. Assessments of cell rolling were made at 1.5 dynes/cm2 from the midpoint of the chamber viewing field (mean ± SEM from four fields per selectin spot and three different experiments). Rolling Th1 cells on E- or P-selectin–Ig were inhibitable with 0.5 mM EDTA, and rolling adhesions on human IgG–coated plastic were absent. *P < 0.001, Student’s paired t test. Neur, neuraminidase.