Immunological functions of hyaluronan and its receptors in the lymphatics

The lymphatic system is best known for draining interstitial fluid from the tissues and returning it to the blood circulation. However, the lymphatic system also provides the means for immune surveillance in the immune system, acting as conduits that convey soluble antigens and antigen-presenting cells from the tissues to the lymph nodes, where primary lymphocyte responses are generated. One macromolecule that potentially unites these two functions is the large extracellular matrix glycosaminoglycan hyaluronan (HA), a chemically simple copolymer of GlcNAc and GlcUA that fulfills a diversity of functions from danger signal to adhesive substratum, depending upon chain length and particular interaction with its many different binding proteins and a small but important group of receptors. The two most abundant of these receptors are CD44, which is expressed on leukocytes that traffic through the lymphatics, and LYVE-1, which is expressed almost exclusively on lymphatic endothelium. Curiously, much of the HA within the tissues is turned over and degraded in lymph nodes, by a poorly understood process that occurs in the medullary sinuses. Indeed there are several mysterious aspects to HA in the lymphatics. Here we cover some of these by reviewing recent findings in the biology of lymphatic endothelial cells and their possible roles in HA homeostasis together with fresh insights into the complex and enigmatic nature of LYVE-1, its regulation of HA binding by sialylation and self-association, and its potential function in leukocyte trafficking.