title: Binding of Hyaluronan to the Native Lymphatic Vessel Endothelial Receptor LYVE-1 Is Critically Dependent on Receptor Clustering and Hyaluronan Organization.
abstract: The lymphatic endothelial receptor LYVE-1 has been implicated in both uptake of hyaluronan (HA) from tissue matrix and in facilitating transit of leukocytes and tumor cells through lymphatic vessels based largely onin vitrostudies with recombinant receptor in transfected fibroblasts. Curiously, however, LYVE-1 in lymphatic endothelium displays little if any binding to HAin vitro, and this has led to the conclusion that the native receptor is functionally silenced, a feature that is difficult to reconcile with its proposedin vivofunctions. Nonetheless, as we reported recently, LYVE-1 can function as a receptor for HA-encapsulated Group A streptococci and mediate lymphatic dissemination in mice. Here we resolve these paradoxical findings and show that the capacity of LYVE-1 to bind HA is strictly dependent on avidity, demanding appropriate receptor self-association and/or HA multimerization. In particular, we demonstrate the prerequisite of a critical LYVE-1 threshold density and show that HA binding may be elicited in lymphatic endothelium by surface clustering with divalent LYVE-1 mAbs. In addition, we show that cross-linking of biotinylated HA in streptavidin multimers or supramolecular complexes with the inflammation-induced protein TSG-6 enables binding even in the absence of LYVE-1 cross-linking. Finally, we show that endogenous HA on the surface of macrophages can engage LYVE-1, facilitating their adhesion and transit across lymphatic endothelium. These results reveal LYVE-1 as a low affinity receptor tuned to discriminate between different HA configurations through avidity and establish a new mechanistic basis for the functions ascribed to LYVE-1 in matrix HA binding and leukocyte traffickingin vivo.
authors.affiliation: From the MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, United Kingdom and.
authors.forename: William
authors.initials: W
authors.lastname: Lawrance
authors.affiliation: From the MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, United Kingdom and.
authors.forename: Suneale
authors.initials: S
authors.lastname: Banerji
authors.affiliation: the Wellcome Trust Centre for Cell Matrix Research, Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, United Kingdom.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Day
authors.affiliation: From the MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, United Kingdom and.
authors.forename: Shaumick
authors.initials: S
authors.lastname: Bhattacharjee
authors.affiliation: From the MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, United Kingdom and david.jackson@imm.ox.ac.uk.
authors.forename: David G
authors.initials: DG
authors.lastname: Jackson
mesh_terms: D000328:Adult; D000818:Animals; D002448:Cell Adhesion; D002465:Cell Movement; D002478:Cells, Cultured; D004729:Endothelium, Lymphatic / Q000166:cytology* / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D018960:Hyaluronan Receptors; D006820:Hyaluronic Acid / Q000378:metabolism*; D019169:Jurkat Cells; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D055503:Protein Multimerization; D033921:Vesicular Transport Proteins / Q000378:metabolism*
chemical_list: D018960:Hyaluronan Receptors; C119248:LYVE1 protein, human; D033921:Vesicular Transport Proteins; D006820:Hyaluronic Acid
keywords: LYVE-1; TSG-6; cell adhesion; complex; endothelial cell; extracellular matrix; hyaluronan; lymphatic endothelium; macrophage; transmigration
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