Johnson LA, Clasper S, Holt AP, Lalor PF, Baban D, Jackson DGAn inflammation-induced mechanism for leukocyte transmigration across lymphatic vessel endothelium. J Exp Med 203:2763-2777

Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, and Institute of Biomedical Research, MRC Centre for Immune Regulation, University of Birmingham Medical School, UK.
Journal of Experimental Medicine (Impact Factor: 12.52). 12/2006; 203(12):2763-77. DOI: 10.1084/jem.20051759
Source: PubMed


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 alpha 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.

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    • "Complementary roles in cDC migration have been suggested for other chemokine receptors and S1P1/S1P3 signaling, but CCR7 seems to be the major player. Integrins, on the other hand, are dispensable for the migration of cDCs to LNs under physiological conditions (Lä mmermann et al., 2008) but are needed for optimal migration during contact sensitization (Johnson et al., 2006). "
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    • "PECAM (CD31) is a molecule expressed on most endothelial cells and involved in leukocyte extra- and intravasation (112). LVs express less CD31 (113) than their blood counterparts and it is mostly distributed at cell–cell homotypic interactions (17, 29). Studies made with human cells have shown that blocking this molecule as well as CD99 in CXCL12 treated LEC was able to reduce TEM, both in vitro and on ex vivo tissue cultures (62). "
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    • "In the steady state, lymphatic capillaries express little to no ICAM-1 and VCAM-1 (Johnson et al., 2006) and adoptively transferred integrindeficient DCs migrate to the LN normally (Lammermann et al., 2008). However, ICAM-1 and VCAM-1 are upregulated during inflammation (Johnson et al., 2006) and are needed for optimal migration of DCs to LNs during contact sensitization (Johnson et al., 2006; Ma, Wang, Guo, Sy, & Bigby, 1994; Xu et al., 2001), along with other adhesive cues (Fig. 2.2). Delineating the distinct requirements for DC migration under inflammatory and resting conditions and the underlying reasons why the requirements are different under these conditions requires more research. "
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