Glycosaminoglycan chemokine interactions

Figure 4.1. Schematic representation of leukocyte transmigration induced by chemokines. The first step involves rolling attributed to interaction between the leukocyte and the endothelial cells. This process is mediated by selectins and selectin ligands expressed on the surface of both cell types. In the next step a chemokine interacts with its receptor, inducing leukocyte activation and conformational changes in the adhesion molecules (integrins) and resulting in firm adhesion to the endothelial surface. It is believed that the chemokine is immobilized on the endothelial surface by interactions with glycosaminoglycans. The leukocytes then transmigrate into the tissues.

Johnson Z, Proudfoot AE, Handel TM (2005) Interaction of chemokines and glycosaminoglycans a new twist in the regulation of chemokine function with opportunities for therapeutic intervention. Cytokine Growth Factor Rev 16 625-636 Jones G, Power C (2006) Regulation of neural cell survival by HIV-1 infection. Neurobiol Dis 21 1-17... 

Kuschert, G.S., F. Coulin, C.A. Power, A.E. Proudfoot, R.E. Hubbard, A.J. Hoogewerf, and T.N. Wells. 1999. Glycosaminoglycans interact selectively with chemokines and modulate receptor binding and cellular responses. Biochemistry 38 12959-12968. 

Chemokine-Receptor Interactions GPCRs, Glycosaminoglycans and Viral Chemokine Binding 11- n Proteins... 

While it was always well accepted that chemokines need to be immobilized on the endothelial surface through their interaction with glycosaminoglycans (GAGs) in order to provide a directional signal, direct evidence was provided by the loss of the ability to recruit cells in vivo by chemokine mutants with abrogated GAG-binding capacity (Proudfoot et al., 2003). 

Finally, posttranslational modification of chemokines is another level of complexity when trying to understand the effects of chemokines in vivo. Recruited leukocytes and the inflamed tissue are a rich source of different enzymes that alter the structure of chemokines, changing their interaction with receptors and glycosaminoglycans and modifying their actions. Proteolysis, glycosylation, citrullination, and nitration are examples of how chemokines can be modified (Mortier et al., 2012). For instance, CD26 (also known as dipeptidylpeptidase 4) is a protease that can remove the first two amino acids from a protein that possesses a proHne or alanine in the... 

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