Accumulation and turnover of extracellular matrix components are the hallmarks of tissue injury. Fragmented hyaluronan stimulates the expression of inflammatory genes by a variety of immune cells at the injury site. Hyaluronan binds to a number of cell surface proteins on various cell types. Hyaluronan fragments signal through both Toll-like receptor (TLR) 4 and TLR2 as well as CD44 to stimulate inflammatory genes in inflammatory cells. Hyaluronan is also present on the cell surface of epithelial cells and provides protection against tissue damage from the environment by interacting with TLR2 and TLR4. Hyaluronan and hyaluronan-binding proteins regulate inflammation, tissue injury, and repair through regulating inflammatory cell recruitment, release of inflammatory cytokines, and cell migration. This review focuses on the role of hyaluronan as an immune regulator in human diseases.

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Hyaluronan as an Immune Regulator in Human Diseases

Hyaluronan (HA) is a prominent component of the extracellular matrix at many sites of chronic inflammation, including type 1 diabetes (T1D), multiple sclerosis, and numerous malignancies Recent publications have demonstrated that when HA synthesis is inhibited using 4-methylumbelliferone (4-MU), beneficial effects are observed in several animal models of these diseases Notably, 4-MU is an already approved drug in Europe and Asia called "hymecromone" where it is used to treat biliary spasm However, there is uncertainty regarding how 4-MU treatment provides benefit in these animal models and the potential long-term consequences of HA inhibition Here, we review what is known about how HA contributes to immune dysregulation and tumor progression Then, we review what is known about 4-MU and hymecromone in terms of mechanism of action, pharmacokinetics, and safety Finally, we review recent studies detailing the use of 4-MU to treat animal models of cancer and autoimmunity

/pdf/4-methylumbelliferone-treatment-and-hyaluronan-inhibition-as-4gj2fgofg2.pdf

4-methylumbelliferone treatment and hyaluronan inhibition as a therapeutic strategy in inflammation, autoimmunity, and cancer

Hyaluronan as a therapeutic target in human diseases.

Hyaluronan synthase 1 (HAS1) requires higher cellular UDP-GlcNAc concentration than HAS2 and HAS3.

Low molecular weight hyaluronan activates cytosolic phospholipase A2α and eicosanoid production in monocytes and macrophages.

Accumulation of hyaluronan (HA) around smooth muscle cells in lesions of atherosclerosis in diabetic patients suggests that this protein plays an important role in diabetic angiopathy. The aim of this study was to determine the correlation between serum HA concentrations and diabetic angiopathy. Diabetic patients treated with or without an oral hypoglycemic agent and/or insulin for at least 1 year were recruited (n = 95). We also included 20 non-diabetic control subjects. We measured serum levels of HA, body mass index (BMI), fasting plasma glucose (FPG), HbA1c, total cholesterol, triglyceride, glycated albumin (GA), high sensitivity CRP (hs-CRP), monocyte chemoattractant protein (MCP)-1 and evaluated diabetes mellitus history, drug use and presence of related complications. Serum HA levels were significantly (P<0.05) higher in diabetic patients (83.6 +/- 5.6 ng/ml, mean +/- SEM) than in normal subjects (41.7 +/- 12 ng/ml). In diabetic patients, serum HA concentration significantly correlated with FPG, HbA1c, GA, triglyceride and also significantly correlated with BMI, hs-CRP and MCP-1 and tended to be higher in diabetic patients with complications than in those without such complications. Our data suggest that serum HA level correlates with poor blood glucose control and diabetic angiopathy and that it could be used as a marker of diabetic angiopathy.

Shinichiro Mine

Papers

Serum hyaluronan concentration as a marker of angiopathy in patients with diabetes mellitus.