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.
View: Text | PDF
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

×

Figure 4

Options: View larger image (or click on image) Download as PowerPoint
Effects of 4-F-GlcNAc on antigen presentation in regional skin-draining ...
Effects of 4-F-GlcNAc on antigen presentation in regional skin-draining LNs. Following a 4-day intraperitoneal pretreatment with diluent control or with 50, 100, or 250 mg 4-F-GlcNAc, mice were sensitized on the right ear with 0.5% FITC (acetone/dibutyl phthalate, 1:1) and on the left ear with vehicle alone. After 30 hours, DC-enriched cells from ipsilateral cervical/auricular nodes from three mice were stained with PE–anti-CD11c mAb for flow cytometry. Representative histograms of green fluorescence (FITC) of CD11c+ cells from DC-enriched cells prepared from skin-draining LNs of the left side or from contralateral skin-draining LNs of the right side illustrate the increased level of FITC-expressing DCs from LNs draining right FITC-sensitized ears. Data show a lack of dose response due to 4-F-GlcNAc treatment, though a slight increase in DCs staining positive for FITC was observed in all 4-F-GlcNAc–treated mice. Percent positive FITC expression is indicated in diluent control by subtracting gates R8 from R7 (8%); in 50 mg/kg 4-F-GlcNAc by subtracting gates R10 from R9 (12%); in 100 mg/kg 4-F-GlcNAc by subtracting gates R12 from R11 (13%); and in 250 mg/kg 4-F-GlcNAc by subtracting gates R14 from R13 (10%). These data are representative of three independent experiments.