Understanding the mechanisms that facilitate specificity, not redundancy, of chemokine-mediated leukocyte recruitment

Abstract

Chemokines (chemotactic cytokines) and their receptors are critical to recruitment and positioning of cells during development and the immune response. The chemokine system has long been described as redundant for a number of reasons, where multiple chemokine ligands can bind to multiple receptors and vice versa. This apparent redundancy has been thought to be a major reason for the failure of drugs targeting chemokines during inflammatory disease. We are now beginning to understand that chemokine biology is in fact based around a high degree of specificity, where each chemokine and receptor plays a particular role in the immune response. This specificity hypothesis is supported by a number of recent studies designed to address this problem. This review will detail these studies and the mechanisms that produce this specificity of function with an emphasis on the emerging role of chemokine-glycosaminoglycan interactions.

Keywords: chemokine/chemokine receptors; chemokines; chemotaxis; inflammation.

Figure 1

Specificity of the chemokine system and the mechanisms that produce it. Chemokine ligands can bind to various chemokine receptors and vice versa. In addition, the same receptor can be expressed by different types of immune cell. This has classically led to the idea of redundancy in the system. Detailed analysis has demonstrated that the chemokine system is in fact based around specificity of receptor and ligand function. This is produced by a number of mechanisms. (1) Differential receptor and ligand expression to localize signals. (2) Biased signalling, where different ligands can produce different signalling outcomes via the same receptor. (3) Differential interaction with glycosaminoglycans that are present within vascular and tissue extracellular matrix. Together these mechanisms facilitate specific function of each chemokine ligand and receptor during immune cell recruitment.

Figure 2

Heparan sulphate proteoglycan structure. Heparan sulphate (HS) proteoglycans have a protein core that is cell membrane embedded, as depicted here (syndecan 1–4 and glypican 1–6), or soluble (serglycin and agrin) decorated with sugar side chains. These HS sugar side chains are attached to a serine residue and have an initial linker followed by repeating disaccharide units of glucuronic acid (GlcA) and N‐acetyl‐d‐glucosamine (GlcNAc). GlcA can be epimerized to iduronic acid (IdoA) and sulphated at the C‐2 position. GlcNAc can be N‐sulphated to GlcNS, with sulphate groups also added at C‐6 and sometimes C‐3. Proteoglycans can cluster together to form a glycocalyx on different cell types. In particular, the endothelial glycocalyx, largely composed of proteoglycans, forms a barrier that controls blood vessel permeability and immune cell migration.