Inflammation-induced uptake and degradation of the lymphatic endothelial hyaluronan receptor LYVE-1.

Abstract

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.

• Authors: Louise A Johnson, Remko Prevo, Steven Clasper, David G Jackson
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 282 Issue 46 Pg. 33671-33680 (Nov 16 2007) ISSN: 0021-9258 [Print] United States
• PMID: 17884820 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Allergens
• Glycoproteins
• LYVE1 protein, human
• Membrane Transport Proteins
• Vascular Cell Adhesion Molecule-1
• Vesicular Transport Proteins
• Xlkd1 protein, mouse
• Hyaluronic Acid

Topics

• Allergens (chemistry)
• Animals
• Cell Adhesion
• Gene Expression Regulation
• Glycoproteins (metabolism)
• Humans
• Hyaluronic Acid (metabolism)
• Inflammation
• Leukocytes (metabolism)
• Lymphangiogenesis
• Lymphatic System (metabolism)
• Lysosomes (metabolism)
• Male
• Membrane Transport Proteins
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Vascular Cell Adhesion Molecule-1 (metabolism)
• Vesicular Transport Proteins (metabolism)