The Complex Role of Heparan Sulfate in Regulating Inflammation

 

New Insights into Heparan Sulfate and Leukocyte Navigation

During inflammation, loss of heparan sulfate from the endothelial glycocalyx facilitates interactions with leukocytes, resulting in their recruitment to inflammatory sites.

Adhesion molecules provide a molecular brake for leukocytes circulating through the blood stream. The glycocalyx is a proteoglycan shield on endothelial cells of blood vessels that impinge adhesion molecule interactions between the endothelium and circulating white blood cells. During inflammation, when white blood cells need to leave the blood and enter tissues to fight infections, heparan sulfate is actively decreased from the endothelial glycocalyx to facilitate leukocyte interactions with the endothelium and promote their recruitment and movement into inflammatory sites.

A recent report in Science Signaling by Priestley and colleagues used a mouse model of psoriasis, an autoimmune inflammatory disease of the skin, to demonstrate that heparan sulfate is present not just on the glycocalyx of the endothelium, but is also found on the cell surfaces of circulating leukocytes. Thus, recruitment of white blood cells involves interactions with glycosaminoglycans on both blood vessels and leukocytes to successfully navigate into inflamed tissues. Priestley found that leukocyte recruitment into the skin is mediated in part by heparanase secreted by white blood cells, which cleaves heparan sulfates specifically on leukocytes and not endothelial cells. Further, blockade of heparanase cleavage of heparan sulfate reduced leukocyte infiltration while paradoxically increasing inflammation due to decreased numbers of recruited T regulatory cells. Taken together, these data illustrate the highly complex signaling required for recruitment and spatial localization of immune cells in inflamed tissues during infection and autoimmune responses. Heparan sulfate plays a highly refined role as a gatekeeper in regulating inflammation.