Syndecans in Inflammation at a Glance

Abstract

Syndecans are transmembrane proteoglycans with heparan and chondroitin sulfate chains attached to their extracellular domain. Like many proteoglycans, they interact with a large number of ligands, such as growth factors, adhesion receptors, soluble small molecules, proteinases, and other extracellular matrix proteins to initiate downstream signaling pathways. Syndecans play a major role in inflammation, mainly by regulating leukocyte extravasation and cytokine function. At the same time, syndecans can undergo cytokine mediated changes in their expression levels during inflammation. The function of syndecans during inflammation appears to depend on the stage of inflammation, sulfation of heparan/chondroitin sulfate chains, the rate of ectodomain shedding and the solubility of the ectodomains. From the current literature, it is clear that syndecans are not only involved in the initial recruitment of pro-inflammatory molecules but also in establishing a balanced progression of inflammation. This review will summarize how cell surface and soluble syndecans regulate multiple aspects of inflammation.

Keywords: chemokine gradient; cytokines; extravasation; inflammation; proteoglycan; shedding; syndecan.

Figure 1

Role of syndecans in extravasation. Syndecans bind to inflammatory cytokines and chemokines through GAG chains. This interaction appears to trigger a feedback signaling, which results in an elevated expression of both syndecan and cytokines. The GAG chain mediated binding of syndecan with chemokine and the subsequent shedding of syndecan-chemokine complex results in a stable chemokine gradient. Syndecans mediate a loose interaction between leukocytes and endothelial cells through selectins, which reduces the pace of leukocyte movement and they bigin to roll over the vessel surface. The adhesion between leukocytes and endothelial cells is strengthened by an integrin controlled signaling and other cell adhesion molecules, leading to the arrest of leukocyte rolling. Attached leukocytes begin transmigration directed by a stable chemokine gradient to the site of inflammation.