Hyaluronan and Its Receptors: Key Mediators of Immune Cell Entry and Trafficking in the Lymphatic System

Abstract

Entry to the afferent lymphatics marks the first committed step for immune cell migration from tissues to draining lymph nodes both for the generation of immune responses and for timely resolution of tissue inflammation. This critical process occurs primarily at specialised discontinuous junctions in initial lymphatic capillaries, directed by chemokines released from lymphatic endothelium and orchestrated by adhesion between lymphatic receptors and their immune cell ligands. Prominent amongst the latter is the large glycosaminoglycan hyaluronan (HA) that can form a bulky glycocalyx on the surface of certain tissue-migrating leucocytes and whose engagement with its key lymphatic receptor LYVE-1 mediates docking and entry of dendritic cells to afferent lymphatics. Here we outline the latest insights into the molecular mechanisms by which the HA glycocalyx together with LYVE-1 and the related leucocyte receptor CD44 co-operate in immune cell entry, and how the process is facilitated by the unusual character of LYVE-1 • HA-binding interactions. In addition, we describe how pro-inflammatory breakdown products of HA may also contribute to lymphatic entry by transducing signals through LYVE-1 for lymphangiogenesis and increased junctional permeability. Lastly, we outline some future perspectives and highlight the LYVE-1 • HA axis as a potential target for immunotherapy.

‘Two-faces’ of hyaluronan, a dynamic barometer of disease progression in tumor microenvironment

“…In addition, increasing the secretion of soluble CD44 in lung metastases of breast cancer can stimulate the interstitial tissue to produce a large amount of HMW-HA, forming a physical barrier and inhibiting the colonization of metastatic cells [ 86 ]. Besides, when HMW-HA binds to LYVE-1, the permeability and integration of lymphatic endothelial cells are broken down in tumor tissues [ 88 , 89 ].…”

Lymphangiogenesis and Lymphatic Barrier Dysfunction in Renal Fibrosis

“…On one hand, LVs are responsible for uptake and transport of immune cells from tissues to lymph nodes for following inflammatory response, and on the other hand, inflammatory factors influence the function of LVs, including vascular permeability and pumping activity [27]. After synthesizing and assembling hyaluronic acid glycocalyx on the surface, immune cells can provide the hyaluronan by themselves to adhere lymphatic vessel endothelial protein(LYVE-1), therefore docking to LECs [28]. Although there is extensive evidence that hyaluronic acid influences endothelial permeability, most of them are based on vascular endothelium [29][30][31], not lymphatic endothelium.…”

Atomic-Resolution Experimental Structural Biology and Molecular Dynamics Simulations of Hyaluronan and Its Complexes

“…Expanding this structural biology knowledge has the potential to improve mechanistic understanding of hyaluronan biology, which consists principally of contributions to extra- and peri-cellular structure and associated signaling pathways [ 3 , 4 , 5 , 6 , 7 ], although recent findings also point to intracellular roles [ 8 ]. Consequences of this structure and signaling have bearing on aging [ 9 , 10 , 11 , 12 , 13 , 14 ], inflammation [ 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 ], wound healing [ 24 , 25 , 26 , 27 ], and cancer [ 28 , 29 , 30 , 31 , 32 , 33 , 34 ].…”