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 alpha1,3-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
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 112 Issue 7 Pg. 1008-18 (Oct 2003) ISSN: 0021-9738 [Print] United States
• PMID: 14523038 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antigens, Differentiation, T-Lymphocyte
• Antigens, Neoplasm
• CTAGE1 protein, human
• E-Selectin
• Membrane Glycoproteins
• P-Selectin
• P-selectin ligand protein
• 2-acetamido-1,3,6-tri-O-acetyl-4-deoxy-4-fluoroglucopyranose
• Acetylglucosamine

Topics

• Acetylglucosamine (analogs & derivatives, pharmacology)
• Animals
• Antigen Presentation (drug effects)
• Antigens, Differentiation, T-Lymphocyte
• Antigens, Neoplasm
• Cell Movement (drug effects)
• Dermatitis, Contact (prevention & control)
• E-Selectin (metabolism)
• Membrane Glycoproteins (metabolism)
• Mice
• P-Selectin (metabolism)
• Skin (immunology)
• T-Lymphocytes (physiology)