Abstract
The primary function of chemokines is to direct the migration of leukocytes to the site of injury during inflammation. The effects of chemokines are modulated by several means, including binding to G-protein coupled receptors (GPCRs), binding to glycosaminoglycans (GAGs), and through post-translational modifications (PTMs). GAGs, present on cell surfaces, bind chemokines released in response to injury. Chemokines bind leukocytes via their GPCRs, which directs migration and contributes to local inflammation. Studies have shown that GAGs or GAG-binding peptides can be used to interfere with chemokine binding and reduce leukocyte recruitment. Post-translational modifications of chemokines, such as nitration, which occurs due to the production of reactive species during oxidative stress, can also alter their biological activity. This review describes the regulation of chemokine function by GAG-binding ability and by post-translational nitration. These are both aspects of chemokine biology that could be targeted if the therapeutic potential of chemokines, like CXCL8, to modulate inflammation is to be realised.
Highlights
Chemokines are small cytokines (8–17 kDa) with chemoattractant properties that are involved in processes ranging from homeostasis to development and tissue repair
The migration of immune cells is mediated through the formation of dynamic chemokine gradients, which are achieved by the binding of chemokines on glycosaminoglycans (GAGs) present on the surface of endothelial cells and in the extracellular matrix [6]
Nitrated CXCL12 binds GAGs with a similar affinity as wild type CXCL12 [90], but nitrated CCL2 has been shown to have reduced ability to bind both heparin and heparan sulphate when compared to wild type CCL2 [92]
Summary
Chemokines are small cytokines (8–17 kDa) with chemoattractant properties that are involved in processes ranging from homeostasis to development and tissue repair. The migration of immune cells is mediated through the formation of dynamic chemokine gradients, which are achieved by the binding of chemokines on glycosaminoglycans (GAGs) present on the surface of endothelial cells and in the extracellular matrix [6] This creates an equilibrium of free and bound monomer and dimer in the proximity of the injury, resulting in haptotactic and chemotactic gradients. Upon regeneration of the glycocalyx, upregulation of the expression of NDST enzymes increases the extent of N-sulphation, which in turn enhances the potential of the endothelium to bind and present pro-inflammatory chemokines [50] This highlights the flexibility and varied regulation of endothelial GAGs and their ability to modulate chemokine binding and subsequent leukocyte migration. Due to heparin’s uniform sulphation pattern, and the commercial availability of size-fractionated oligosaccharides of many different sizes, heparin is commonly used for structure—function and chemokine-GAG interaction studies
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