Differential structural remodelling of heparan sulfate by chemokines: the role of chemokine oligomerization

Dyer, D. P. , Migliorini, E., Salanga, C. L., Thakar, D., Handel, T. M. and Richter, R. P. (2017) Differential structural remodelling of heparan sulfate by chemokines: the role of chemokine oligomerization. Open Biology, 7, 160286. (doi: 10.1098/rsob.160286)

[img]
Preview
Text
133453.pdf - Published Version
Available under License Creative Commons Attribution.

1MB

Abstract

Chemokines control the migration of cells in normal physiological processes and in the context of disease such as inflammation, autoimmunity and cancer. Two major interactions are involved: (i) binding of chemokines to chemokine receptors, which activates the cellular machinery required for movement; and (ii) binding of chemokines to glycosaminoglycans (GAGs), which facilitates the organization of chemokines into haptotactic gradients that direct cell movement. Chemokines can bind and activate their receptors as monomers; however, the ability to oligomerize is critical for the function of many chemokines in vivo. Chemokine oligomerization is thought to enhance their affinity for GAGs, and here we show that it significantly affects the ability of chemokines to accumulate on and be retained by heparan sulfate (HS). We also demonstrate that several chemokines differentially rigidify and cross-link HS, thereby affecting HS rigidity and mobility, and that HS cross-linking is significantly enhanced by chemokine oligomerization. These findings suggest that chemokine–GAG interactions may play more diverse biological roles than the traditional paradigms of physical immobilization and establishment of chemokine gradients; we hypothesize that they may promote receptor-independent events such as physical re-organization of the endothelial glycocalyx and extracellular matrix, as well as signalling through proteoglycans to facilitate leukocyte adhesion and transmigration.

Item Type:Articles
Additional Information:This work was supported, in whole or in part, by National Institutes of Health grant nos. R01 AI118985, R21 AI121918 and R21 AI122211 (to T.M.H.), by the Nanoscience Foundation (Grenoble, France) Chair of Excellence Project ‘GAG2D’ (to R.P.R.), the European Research Council starting grant ‘JELLY’ (FP7-ERC-2012-StG-306435, to R.P.R.) and the Spanish Ministry for Economy and Competitive- ness (Retos grant no. MAT2014–54867-R, to R.P.R.).
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Dyer, Dr Douglas
Authors: Dyer, D. P., Migliorini, E., Salanga, C. L., Thakar, D., Handel, T. M., and Richter, R. P.
College/School:College of Medical Veterinary and Life Sciences > School of Infection & Immunity
Journal Name:Open Biology
Publisher:The Royal Society
ISSN:2046-2441
ISSN (Online):2046-2441
Published Online:25 January 2017
Copyright Holders:Copyright © 2017 The Authors
First Published:First published in Open Biology 7:160286
Publisher Policy:Reproduced under a Creative Commons License

University Staff: Request a correction | Enlighten Editors: Update this record