of HA.35,36 Association of HA with CD44, and to a lesser extent interaction with lymphatic vessel endothelial hyaluronan receptor-
1 and hyaluronan-mediated motility receptor (RHAMM), also determines cell proliferation and differentiation during wound healing and inflammation.37-40 The role of intracellular HA is less understood, but its presence has been linked to hyperglycemic conditions and emergency-room stress.41-44 A potential role in cell division has also been proposed as intracellular HA and its receptor (RHAMM) co-localized with different structures of the spindle apparatus during mitosis, which may regulate nucleolar function or chromosomal rearrangements.12,45
Under physiological conditions, most of the HA in the skin is high MW, though exposure to UV radiations as well as tissue injury may trigger HA fragmentation. Fragmented HA activates signal transduction pathways that control migration, survival, and re-differentiation in dermal fibroblasts and keratinocyte.46-49 The differential functions observed between native and fragmented
HA (Figure 1) can be attributed to selective interactions with specific receptors, which are controlled by the size of the polymer.4 One of the most important non-hydrating functions of high-MW HA is its capacity to prevent uncontrolled inflammation
by inhibiting macrophages proliferation and cytokine production during early response to injury, promoting wound
healing.6,50,51 HA also increases proteoglycan synthesis, reduces
production of and inactivates pro-inflammatory mediators, blocks activation of nicotinamide adenine dinucleotide phosphate
oxidase by antigen stimulation and metalloproteinase expression, alters the function of immune cells, and acts as a free radical scavenger.52-55 The latter is accomplished by the capacity of the double bond in the D-glucoronic acid unit to complex with reactive molecules.56 In response to cellular stress, inflammation, and viral infections, HA also forms leukocytes
pro-adhesive cable-like structures when cross-linked to versican, heavy-chain molecules originated from inter-α-trypsin inhibitor and the complex TSG-6 and pentaxin-3.57-59
Interactions between CD44 and HA are also responsible for the modulation of T-cell function, though this interaction does not occur constitutively (resting T-cells do not bind HA). The formation
of CD44-HA complexes is observed only in activated T-cells, which stimulate their extravasation into inflammatory sites60 and trigger the suppressor activity of CD4+CD25+ regulatory T-cells.61 The mechanisms that regulate this very selective interactions
are not fully understood, but it is likely to be mediated by post-transcriptional modifications of CD44 (ie, glycosylation, chondroitin sulfate addition, sulfation, or removal of sialic acid motifs). In recent years, it has been shown that cholesterol
