Leukocyte Adhesion: Reconceptualizing Chemokine Presentation by Glycosaminoglycans.

Recruitment of immune cells from the vasculature relies on the presentation of glycosaminoglycan-bound chemokines on the luminal side of vascular endothelial cells. However, the current model of chemokine–glycosaminoglycan interactions, and its implications for receptor interactions, remains poorly developed. We propose a refined 'Chemokine Cloud' model, arguing that chemokines are not presented to leukocytes bound to glycosaminoglycans, but rather, in solution while sequestered within the hydrated glycocalyx. We posit that glycosaminoglycans provide an immobilized chemokine depot maintaining a 'cloud' of 'solution-phase' chemokines within the glycocalyx, and that it is this soluble form of any given chemokine that interacts with leukocyte-bound receptors. Our proposition clarifies certain anomalies associated with the current model of chemokine–glycosaminoglycan interactions, with implications for the design of blockers of chemokine function. Recent chemokine receptor structures indicate that oligomerization of chemokines, which is important for chemokine–GAG interactions, is incompatible with receptor binding. Receptor–ligand structures are incompatible with a model of direct presentation of ligand bound to GAGs. Recent in vivo data suggest that antichemokine antibodies targeting chemokines in 'soluble phase', rather than attached to GAGs, can be more effective in ameliorating certain inflammatory conditions. [ABSTRACT FROM AUTHOR]