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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Allergic CHS in mice treated with 4-F-GlcNAc. (a) Wild-type mice were se...
Allergic CHS in mice treated with 4-F-GlcNAc. (a) Wild-type mice were sensitized on the abdomen with 0.5% DNFB in vehicle (acetone/olive oil, 4:1) on days 0 and 1. Mice were given 0.9% saline (diluent), 50, 100, or 250 mg/kg 4-F-GlcNAc, 5 mg/kg swainsonine, or 250 mg/kg GlcNAc (negative drug control) intraperitoneally daily from day 1 to day 6. FucTIV/VII–null mice were also sensitized with 0.5% DNFB and treated with diluent control. Mice were then challenged on the right ear on day 6 with 0.25% DNFB and on the left ear with vehicle alone. After 24 hours, ear swelling was determined by measurement of ear thickness, which was subtracted from base-line ear-thickness measurements. *P < 0.0002, Student’s paired t test. ND, not determined. (b) Wild-type mice were sensitized on the abdomen with 0.5% DNFB on days 0 and 1. Mice were given diluent control or 50 or 100 mg/kg 4-F-GlcNAc intraperitoneally daily either from day 1 to day 6 or from day 6 to day 11. Mice were then challenged on the right ear on day 11 with 0.25% DNFB and on the left ear with vehicle alone. After 24 hours, ear swelling was determined. *P < 0.007, Student’s paired t test. Data in a and b represent mean ear swelling ± SEM from eight mice per group and three experiments. (c) Representative photomicrographs of H&E-stained sections from ears of mice sensitized and challenged with 0.5% DNFB illustrate differences in ear thickness between mice treated with diluent control and with 4-F-GlcNAc. ×200 magnification. Bar: 100 μm.