Lookup NU author(s): Beatriz Martinez Burgo,
Professor John Kirby,
Professor Neil Sheerin,
Professor Simi Ali
This is the authors' accepted manuscript of an article that has been published in its final definitive form by Wiley-Blackwell, 2019.
For re-use rights please refer to the publisher's terms and conditions.
Leukocyte recruitment is critical during many acute and chronic inflammatory diseases. Chemokines are key mediators of leukocyte recruitment during the inflammatory response, by signaling through specific chemokine G-protein coupled receptors (GPCRs). In addition, chemokines interact with cell surface glycosaminoglycans (GAGs) to generate a chemotactic gradient. The chemokine IL8/CXCL8, a prototypical neutrophil chemoattractant, is characterised by a long, highly positively charged GAG-binding C-terminal region, absent in most other chemokines. In order to examine whether the CXCL8 C-terminal peptide has a modulatory role in GAG binding during neutrophil recruitment, we synthesised the wild type CXCL8 C-terminal [CXCL8 (54-72)] (Peptide 1), a peptide with a substitution of glutamic acid (E) 70 with lysine (K) (Peptide 2) to increase positive charge; and also, a scrambled sequence peptide (Peptide 3). Surface Plasmon Resonance showed that Peptide 1, corresponding to the core CXCL8 GAG-binding region, binds to GAG but Peptide 2 binding was detected at lower concentrations. In the absence of cellular GAG, the peptides did not affect CXCL8 induced calcium signaling or neutrophil chemotaxis along a diffusion gradient, suggesting no effect on GPCR binding. All peptides equally inhibited neutrophil adhesion to endothelial cells under physiological flow conditions. Peptide 2, with its greater positive charge and binding to polyanionic GAG, inhibited CXCL8-induced neutrophil transendothelial migration. Our studies suggest that the E70K CXCL8 peptide, may serve as a lead molecule for further development of therapeutic inhibitors of neutrophil-mediated inflammation based on modulation of chemokine-GAG binding.
Author(s): Martinez-Burgo B, Cobb S, Pohl E, Kashanin D, Paul T, Kirby JA, Sheerin N, Ali S
Publication type: Article
Publication status: Published
Print publication date: 01/06/2019
Online publication date: 23/04/2019
Acceptance date: 05/04/2019
Date deposited: 06/04/2019
ISSN (print): 0019-2805
ISSN (electronic): 1365-2567
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