Abstract
Chemokines control the migration of cells in normal physiological processes and in the context of disease such as inflammation, autoimmunity and cancer. Two major interactions are involved: (i) binding of chemokines to chemokine receptors, which activates the cellular machinery required for movement; and (ii) binding of chemokines to glycosaminoglycans (GAGs), which facilitates the organization of chemokines into haptotactic gradients that direct cell movement. Chemokines can bind and activate their receptors as monomers; however, the ability to oligomerize is critical for the function of many chemokines in vivo. Chemokine oligomerization is thought to enhance their affinity for GAGs, and here we show that it significantly affects the ability of chemokines to accumulate on and be retained by heparan sulfate (HS). We also demonstrate that several chemokines differentially rigidify and cross-link HS, thereby affecting HS rigidity and mobility, and that HS cross-linking is significantly enhanced by chemokine oligomerization. These findings suggest that chemokine–GAG interactions may play more diverse biological roles than the traditional paradigms of physical immobilization and establishment of chemokine gradients; we hypothesize that they may promote receptor-independent events such as physical re-organization of the endothelial glycocalyx and extracellular matrix, as well as signalling through proteoglycans to facilitate leukocyte adhesion and transmigration.
Highlights
Glycosaminoglycans (GAGs) are long chains of repeating saccharide units that get attached to protein cores to form proteoglycans that are either inserted into cell membranes or secreted/shed into the extracellular matrix (ECM) [1,2]
These results provide insight into the potential of chemokines to modify the physical properties of heparan sulfate (HS) chains in the ECM and the glycocalyx, which may reflect an important aspect of chemokine function—modulating the ECM and endothelial cell barrier function to facilitate leukocyte adhesion and transmigration
Cross-linking or clustering of HS proteoglycans is known to have functional effects that result in glycocalyx remodelling and changes in adhesion and barrier permeability to cells [10,12,56], and chemokines would seem to be prime candidates for initiating such a process
Summary
Glycosaminoglycans (GAGs) are long chains of repeating saccharide units that get attached to protein cores to form proteoglycans that are either inserted into cell membranes or secreted/shed into the extracellular matrix (ECM) [1,2]. Along with the ECM, one function of HS and other GAGs in the glycocalyx is to provide structural support for the physical deposition of a wide number of growth factors, cytokines, chemokines and other ECM proteins [4]. More recently this layer has been described as playing a dynamic physical role in controlling the permeability of the endothelium to leukocytes by regulating leukocyte adhesion to the endothelial cells prior to their transmigration through the endothelial cell layer [5 –8].
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