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A C-terminal CXCL8 peptide based on chemokine-glycosaminoglycan interactions reduces neutrophil adhesion and migration during inflammation

Lookup NU author(s): Beatriz Martinez Burgo, Professor John Kirby, Professor Neil Sheerin, Professor Simi Ali

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This is the authors' accepted manuscript of an article that has been published in its final definitive form by Wiley-Blackwell, 2019.

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Abstract

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.


Publication metadata

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

Journal: Immunology

Year: 2019

Volume: 157

Issue: 2

Pages: 173-184

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

Publisher: Wiley-Blackwell

URL: https://doi.org/10.1111/imm.13063

DOI: 10.1111/imm.13063


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