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¹ Medical Research Council (MRC) Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Headington, Oxford OX3 9DS, England, UK
² Liver Research Group, Institute of Biomedical Research, MRC Centre for Immune Regulation, University of Birmingham Medical School, Edgbaston, Birmingham B15 2TT, England, UK
³ MRC Functional Genetics Unit, Department of Human Anatomy and Genetics, University of Oxford, Oxford OX1 3QX, England, UK

CORRESPONDENCE David G. Jackson: djackson{at}hammer.imm.ox.ac.uk

The exit of antigen-presenting cells and lymphocytes from inflamed skin to afferent lymph is vital for the initiation and maintenance of dermal immune responses. How such an exit is achieved and how cells transmigrate the distinct endothelium of lymphatic vessels are unknown. We show that inflammatory cytokines trigger activation of dermal lymphatic endothelial cells (LECs), leading to expression of the key leukocyte adhesion receptors intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and E-selectin, as well as a discrete panel of chemokines and other potential regulators of leukocyte transmigration. Furthermore, we show that both ICAM-1 and VCAM-1 are induced in the dermal lymphatic vessels of mice exposed to skin contact hypersensitivity where they mediate lymph node trafficking of dendritic cells (DCs) via afferent lymphatics. Lastly, we show that tumor necrosis factor stimulates both DC adhesion and transmigration of dermal LEC monolayers in vitro and that the process is efficiently inhibited by ICAM-1 and VCAM-1 adhesion-blocking monoclonal antibodies. These results reveal a CAM-mediated mechanism for recruiting leukocytes to the lymph nodes in inflammation and highlight the process of lymphatic transmigration as a potential new target for antiinflammatory therapy.

Abbreviations used: CAM, cell adhesion molecule; CCL, CC chemokine ligand; CCR, CC chemokine receptor; CMFDA, 5-chloromethylfluorescein diacetate; CXCL, CXC chemokine ligand; ENA-78, epithelial neutrophil activator 78; GRO, growth-regulated oncogene ß; HDLEC, human dermal LEC; ICAM, intercellular adhesion molecule; JAM, junctional adhesion molecule; LEC, lymphatic endothelial cell; LYVE-1, lymph vessel endothelial hyaluronan receptor 1; MCP-1, monocyte chemoattractant protein 1; MDDC, monocyte-derived DC; MDLEC, mouse dermal LEC; MIP-3, macrophage inflammatory protein 3; RANTES, regulated on activation, normal T cell expressed and secreted.

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