Immunologic Roles of Hyaluronan

Abstract

Hyaluronan (HA), a large glycosaminoglycan composed of D-N-acetylglucosamine and D-glucuronic acid, is expressed in virtually all tissues and has long been considered to serve as a structural component or filling material in the tissue interstitium (Filler Theory). This idea was revised with the discovery of HA-binding proteins that introduced the concept that HA may also serve as an adhesive substrate for cellular trafficking (Adhesion Theory). Most recently, it has been shown that HA fragments can deliver maturational signals to dendritic cells (DCs) and high molecular weight HA polymers can deliver costimulatory signals to T-cells (Signaling Theory). Thus, HA may represent an important component of the immune system. Recently, we have evaluated the impact of HA on Langerhans cell (LC) maturation and migration using a novel peptide inhibitor of HA function, termed Pep-1 (GAHWQFNALTVR). As skin-specific members of the DC family, LCs are crucial for the initiation of cutaneous immune responses. Local injections of Pep-1 prevented hapten-induced LC migration from the epidermis, providing the first experimental evidence that HA facilitates their emigration. Moreover, Pep-1 also significantly inhibited the hapten-induced maturation of LCs in vivo as assessed by cell morphology, costimulatory molecule expression, and their ability to induce proliferation of allogeneic T-cells. HA therefore has dual functionality to facilitate LC migration and maturation, the two critical events for the initiation of adaptive immune responses. Finally, we have observed that DC-dependent, antigen-specific T-cell proliferation and cytokine secretion is blocked by Pep-1. These results have revealed a previously unrecognized role for HA in antigen presentation. Thus, far from an inert structural biopolymer, HA represents a multifunctional carbohydrate mediator of immune processes.

Blockade of Hyaluronan Inhibits IL-2-Induced Vascular Leak Syndrome and Maintains Effectiveness of IL-2 Treatment for Metastatic Melanoma

“…The views about its function are rapidly expanding because of the latest explorations. Its functions were summarized as filler theory, adhesion theory, and signaling theory, in which, far from an inert structural biopolymer, HA represents a multifunctional carbohydrate mediator of immune processes (24). Our findings propose that HA could be involved in the pathophysiological process of the endothelial cell damage not only in IL-2-induced VLS but in other endothelial damage-related diseases.…”

“…Pep-1 is a newly isolated peptide that specifically binds to soluble, cell-associated, and immobilized forms of HA. It has been confirmed that Pep-1 inhibits HA function by blocking its molecular interaction with HA-binding proteins (22,24). Figure 1 shows a representative experiment that displayed VLS induced following IL-2 administration in the lungs and liver when compared with the PBS-treated group.…”

“…Inasmuch as HA is involved in lymphocyte homing to organs (24), histopathological studies were conducted to investigate whether the decrease in VLS in Pep-1 treatment was due to the inability of lymphocytes to migrate to the lungs and liver. Mice were injected with PBS, IL-2, Pep-1, or SC as described in Fig.…”

Hyaluronan digestion controls DC migration from the skin

“…For example, DCs express CD44, a major HA binding receptor (40), and this could influence trafficking. However, we showed the ability to rescue the loss of DCs by crossing HYAL1-expressing mice into Tlr4 -/-mice, but this was not seen when crossed into Cd44 -/-mice.…”

Sp1 and Sp3 Mediate Constitutive Transcription of the Human Hyaluronan Synthase 2 Gene

“…HA is synthesized by the HA synthase (HAS) enzymes that are encoded by the corresponding multigene family HAS1, -2, -3a, and -3b (7-10), and its importance in the extracellular matrix is underlined by the expanding range of pathological contexts in which modified or aberrant HA metabolism appears to play a role. These include malignancy, osteoarthritis, and pulmonary and vascular disorders, along with other immune and inflammatory diseases (11)(12)(13)(14)(15)(16)(17)(18)(19). HA has also been implicated in regenerative processes such as wound healing (e.g.…”