Inflammation-induced uptake and degradation of the lymphatic endothelial hyaluronan receptor LYVE-1.
The hyaluronan receptor LYVE-1 is selectively expressed in the endothelium of lymphatic capillaries, where it has been proposed to function in hyaluronan clearance and hyaluronan-mediated leukocyte adhesion. However, recent studies suggest that hyaluronan homeostasis is unperturbed in LYVE-1(-/-) mice and that lymphatic adhesion/transmigration may be largely mediated by ICAM-1 and VCAM-1 rather than LYVE-1. Here we have explored the possibility that LYVE-1 functions during inflammation and report that the receptor is down-regulated by pro-inflammatory cytokines. Using cultured primary lymphatic endothelial cells, we show that surface expression of LYVE-1 is rapidly and reversibly lost after exposure to tumor necrosis factor-alpha (TNFalpha) and TNFbeta via internalization and degradation of the receptor in lysosomes, coupled with a shutdown in gene expression. Curiously, internalization does not result in significant uptake of hyaluronan, a process that is largely insensitive to the novel LYVE-1 adhesion blocking monoclonal antibody 3A, and proceeds almost equally in resting and inflammation-activated lymphatic endothelial cells. Finally, we show that TNF can induce down-modulation of LYVE-1 in ex vivo murine dermal tissue explants and present evidence that the process occurs in vivo, in the context of murine allergen-induced skin inflammation. These findings suggest that LYVE-1 can function independently of hyaluronan and have implications for the use of LYVE-1 as a histological marker for lymphangiogenesis in human pathology.
Johnson
Louise A
LA
Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Headington, Oxford OX3 9DS, United Kingdom.
Prevo
Remko
R
Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Headington, Oxford OX3 9DS, United Kingdom.
Clasper
Steven
S
Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Headington, Oxford OX3 9DS, United Kingdom.
Jackson
David G
DG
Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Headington, Oxford OX3 9DS, United Kingdom. Electronic address: djackson@hammer.imm.ox.ac.uk.
D000485:Allergens / Q000737:chemistry; D000818:Animals; D002448:Cell Adhesion; D005786:Gene Expression Regulation; D006023:Glycoproteins / Q000378:metabolism*; D006801:Humans; D006820:Hyaluronic Acid / Q000378:metabolism; D007249:Inflammation; D007962:Leukocytes / Q000378:metabolism; D042583:Lymphangiogenesis; D008208:Lymphatic System / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism; D008297:Male; D026901:Membrane Transport Proteins; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D033921:Vesicular Transport Proteins / Q000378:metabolism*
D000485:Allergens; D006023:Glycoproteins; D006820:Hyaluronic Acid; D026901:Membrane Transport Proteins; D019010:Vascular Cell Adhesion Molecule-1; D033921:Vesicular Transport Proteins; C119248:LYVE1 protein, human; C492273:LYVE1 protein, mouse