The extracellular matrix glycosaminoglycan hyaluronan (HA) is an abundant component of skin and mesenchymal tissues where it facilitates cell migration during wound healing, inflammation, and em- bryonic morphogenesis. Both during normal tissue homeostasis and particularly after tissue injury, HA is mobilized from these sites through lymphatic vessels to the lymph nodes where it is degraded before entering the circulation for rapid uptake by the liver. Currently, however, the identities of HA binding molecules which control this pathway are unknown. Here we describe the first such molecule, LYVE-1, which we have identified as a major receptor for HA on the lymph vessel wall. The deduced amino acid sequence of LYVE-1 predicts a 322-residue type I integral membrane polypeptide 41% similar to the CD44 HA receptor with a 212-residue extracellular domain containing a single Link module the prototypic HA binding domain of the Link protein superfamily. Like CD44, the LYVE-1 molecule binds both soluble and immobilized HA. However, unlike CD44, the LYVE-1 molecule colocalizes with HA on the luminal face of the lymph vessel wall and is completely absent from blood vessels. Hence, LYVE-1 is the first lymph-specific HA receptor to be characterized and is a uniquely powerful marker for lymph vessels themselves.

IntroductionMacrophages constitute a heterogeneous population of bone marrow-derived cells, present throughout the body, where they perform myriad functions, both during steady-state conditions and in pathology. 1 This is reflected in the variable cell surface phenotypes exhibited by macrophage subsets. Cell surface receptors initiate and orchestrate many of the activities of macrophages, such as growth, differentiation, adhesion, phagocytosis, activation, chemotaxis, and apoptosis. Most such receptors are expressed on other leukocytes, with only a restricted few being exclusive to macrophages and hence implicated in macrophage-specific functions.Sialoadhesin (Sn) is one such receptor. It was originally characterized in the mouse on isolated resident bone marrow macrophages as a nonphagocytic, sialic acid-dependent sheep erythrocyte receptor. 2 In situ, these macrophages bind avidly to developing myeloid and erythroid cells and are therefore well positioned to dispose of apoptotic cells and extruded erythroblast nuclei that are generated during hemopoiesis 3,4 and B lymphopoiesis. 5 Sialylated ligands for Sn are displayed on the surface of the attached hemopoietic cells, and the receptor is clustered at the contact points between macrophages and developing myeloid cells. 6 Sn is therefore likely to be involved in macrophage-hemopoietic cell interactions in the bone marrow. In addition to a scavenging function, resident macrophages may contribute to the trophic microenvironment of the bone marrow, for example, through recycling of heme-derived iron required for sustained erythropoiesis. 7 Immunocytochemical staining of tissue sections showed that Sn is also expressed at high levels on discrete subsets of tissue macrophages, especially those in secondary lymphoid organs. 8 For example, in the spleen of rodents, Sn is expressed mainly on macrophages in the marginal zone, which have been implicated in specialized functions in innate and acquired immunity. 9 Lower levels of Sn were seen on many other tissue macrophage populations, such as in the liver, gut, and lung, and certain macrophage populations, notably the resident brain microglia, expressed undetectable levels of the receptor. 10 Studies on the ED3 antigen in the rat, which has a similar macrophage-restricted distribution, showed that this molecule is the likely rat ortholog of Sn. 11,12 Mature, circulating neutrophils have been shown to express high levels of Sn ligands, whereas other cells such as thymocytes and resting T cells have relatively low levels. 13 Because Sn is not a phagocytic receptor, 2 it is unlikely to be involved directly in scavenging functions, but it could cooperate with phagocytic receptors to increase the efficiency of recognition and uptake as well as being involved in other types of cell-cell interactions. For example, recent findings in a murine model of allogeneic tumor rejection have shown that transferred, activated CD4 and CD8 T cells can cluster in vivo with Sn ϩ macrophages, an association that may be important for T-cell eff...