Glycosaminoglycans and their proteoglycans: host-associated molecular patterns for initiation and modulation of inflammation.

Glycosaminoglycans, linear carbohydrates such as heparan sulfate and hyaluronan, participate in a variety of biological processes including cell-matrix interactions and activation of chemokines, enzymes and growth factors. This review will discuss progress in immunology and the science of wound repair that has revealed the importance of glycosaminoglycans, and their proteoglycans, in the inflammatory process. Heparan sulfate enables growth factor function and modifies enzyme/inhibitor functions, such as antithrombin III and heparin cofactor II. Heparan sulfate also interacts with cytokines/chemokines and participates in leukocyte selectin binding to promote the recruitment of leukocytes. Chondroitin sulfate/dermatan sulfate regulates growth factor activity and is an alternate modulator of heparin cofactor II. In addition, dermatan sulfate induces ICAM-1 expression on endothelial cells and also recruits leukocytes via selectin interactions. Hyaluronan alternatively participates in leukocyte recruitment via interaction with CD44, while activating various inflammatory cells, such as macrophages, through CD44-dependent signaling. Hyaluronan also signals through Toll-like receptor 4 to induce dendritic cell maturation and promote cytokine release by dendritic cells and endothelial cells. Taken together, the field of glycosaminoglycan biology provides new clues and explanations of the process of inflammation and suggests new therapeutic approaches to human disease.