LYVE-1: Unraveling the Mysteries of a Lymphatic Hyaluronan Receptor

Introduction of Hyaluronan

The lymphatic system plays a crucial role in maintaining tissue homeostasis, immune response, and fluid balance in the body. Among the various components that contribute to the intricate functions of the lymphatic system, hyaluronan (HA) stands out as a key player. This polysaccharide is involved in various physiological processes, particularly within the context of the lymphatic system.

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Hyaluronan, a prevalent glycosaminoglycan present in the extracellular matrix of various tissues, serves diverse functions, primarily aiding in cell adhesion and supporting migration. Unlike other glycosaminoglycans, hyaluronan stands alone as a non-branched polysaccharide, forming non-covalent associations with large proteoglycans like aggrecan and versican. These complexes, tethered to chondrocytes, fibroblasts, and epithelial cells via low-affinity interactions with Link superfamily integral membrane receptors, play a crucial role in stabilizing connective tissues such as bone, cartilage, and dermis/epidermis in the skin. Interestingly, degradation products of hyaluronan, specifically oligosaccharides of 100 kDa or less, engage with cells, triggering cellular "activation." This activation leads to the production of inflammatory mediators, vasoactive agents like nitric oxide, and angiogenesis. The distinct biological properties of intact and degraded hyaluronan highlight the compartmentalization of hyaluronan degradation, preventing inappropriate exposure of cells and tissues to the signaling effects induced by hyaluronan fragments.

Fig. 1 Composed of Hyaluronan (PaJiang D., et al. 2011).

LYVE-1 is the Major Lymphatic Hyaluronan Receptor

Lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1), the principal receptor for lymphatic hyaluronan, belongs to the Link protein superfamily and shares a conserved hyaluronan-binding domain known as the "Link" module. Its structure resembles the C-type lectin fold. Identified through homology searches with CD44H, LYVE-1 is a 322-residue integral membrane glycoprotein with a single N-terminal Link module. O-glycosylation leads to its anomalous migration during SDS-PAGE, indicating a larger apparent molecular mass (60-70 kDa) than calculated. LYVE-1 features an unpaired cysteine residue forming an intermolecular disulphide linkage, though its physiological significance is unclear. Anchored to the membrane by a hydrophobic domain, LYVE-1 has a shorter membrane-proximal domain and two N-glycosylation sites in the Link module, both carrying sialylated sugar chains. While 43% similar to CD44 in amino acid sequence, LYVE-1 shows significant homology only in the HA-binding Link module, suggesting divergence post-gene duplication. Functionally, LYVE-1, expressed on cell surfaces or as a soluble Fc fusion protein, specifically binds hyaluronan. Competitive studies with other glycosaminoglycans reveal its high specificity.

The Interaction Mechanism Between LYVE-1 and HA

The interaction between LYVE-1 and hyaluronan (HA) involves intricate mechanisms. LYVE-1, a lymphatic hyaluronan receptor, binds HA through its N-terminal Link module. Experimental evidence suggests that the extent of HA binding is cell-type-dependent and inducible by cell activation. Activating LYVE-1 involves de novo synthesis of a post-translationally modified "active" form, accompanied by shedding of existing receptors. This modification likely includes N-glycan re-modeling, as supported by the blockade of induction with tunicamycin and mutagenesis of N-glycosylation sites while maintaining LYVE-1 conformation. The HA-binding affinity may be influenced by the glycosylation pattern. The detailed regulation of LYVE-1 and HA interaction mirrors similar mechanisms observed in CD44, and further research is needed to precisely understand the glycosylation differences in functionally distinct cells, shedding light on the physiological significance of these interactions.

The Functional of LYVE-1 in Diseases

LYVE-1, a major lymphatic hyaluronan receptor, plays a pivotal role in various diseases due to its involvement in key physiological processes. Its functions are multifaceted, contributing to both homeostasis and pathological conditions across different organ systems.

In cancer, LYVE-1 has emerged as a significant player in tumor progression and metastasis. Tumors often exploit lymphatic vessels for dissemination, and LYVE-1, being a lymphatic receptor, is implicated in this process. Studies have shown elevated LYVE-1 expression in tumor-associated lymphatic vessels, indicating its potential as a diagnostic marker for lymphangiogenesis, a process critical for cancer metastasis. Moreover, LYVE-1's interaction with hyaluronan, a component of the extracellular matrix, influences tumor cell behavior. Aberrant LYVE-1 expression is associated with poor prognosis in certain cancers, emphasizing its clinical relevance.

Inflammatory diseases also demonstrate the involvement of LYVE-1. As an integral part of the lymphatic system, LYVE-1 contributes to immune cell trafficking and the resolution of inflammation. In conditions like rheumatoid arthritis, LYVE-1 may play a role in regulating the influx of immune cells into the synovium. Understanding LYVE-1's dynamics in inflammatory contexts could offer insights into therapeutic interventions targeting lymphatic function.

LYVE-1's role extends to infectious diseases, particularly those involving the lymphatic system. Lymphatic vessels serve as conduits for immune cell trafficking during infections. LYVE-1's participation in this process influences the immune response against pathogens. For instance, in lymphatic filariasis, a parasitic infection affecting the lymphatic system, LYVE-1 may be involved in the host's response to the pathogen. Investigating LYVE-1 in infectious diseases sheds light on the intricate interplay between the lymphatic system and the immune response.

Furthermore, LYVE-1 has implications in cardiovascular diseases. Lymphatic vessels contribute to fluid homeostasis and immune surveillance in the cardiovascular system. LYVE-1's role in maintaining lymphatic vessel integrity is crucial for preventing edema and ensuring efficient drainage of interstitial fluid. Dysfunction of the lymphatic system, including alterations in LYVE-1 expression, is linked to conditions like lymphedema, emphasizing the importance of LYVE-1 in cardiovascular health.

Neurological disorders also exhibit connections to LYVE-1. The lymphatic system in the central nervous system (CNS) has gained attention for its role in waste clearance and immune regulation. LYVE-1, identified in the CNS lymphatic vessels, may contribute to these processes. Investigating the implications of LYVE-1 in neuroinflammation and neurodegenerative diseases offers a novel perspective on the intersection of the lymphatic system and neurological health.

In conclusion, LYVE-1's involvement in different diseases underscores its significance in maintaining homeostasis and responding to pathological conditions. From cancer to inflammatory disorders, infectious diseases, cardiovascular conditions, and neurological disorders, LYVE-1 emerges as a versatile player in diverse physiological processes. Targeting LYVE-1 or modulating its activity may hold therapeutic potential across a spectrum of diseases, making it a promising focus for future research and clinical interventions.

References

1. PaJiang D., et al. Hyaluronan as an immune regulator in human diseases. Physiological Reviews. 2011, 91(1): 221-264.
2. Jackson D G. The lymphatic endothelial hyaluronan receptor LYVE-1. Glycoforum. 2004, 8: A2.