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Interfering with the CCL2-glycosaminoglycan axis as a potential approach to modulate neuroinflammation

Gschwandtner, Martha; Piccinini, Anna Maria; Geriza, Tanja; Adage, Tiziana; Kungl, Andreas

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Authors

Martha Gschwandtner

Tanja Geriza

Tiziana Adage

Andreas Kungl



Abstract

© 2016 Elsevier Ireland Ltd. Multiple Sclerosis, a chronic inflammatory demyelinating disease of the central nervous system, involves an increased expression of monocyte chemotactic protein 1 MCP1-/CCL2. For exerting its chemotactic effects, chemokine binding to glycosaminoglycans (GAGs) is required and therefore this interaction represents a potential target for therapeutic intervention. We have designed an anti-inflammatory decoy variant, Met-CCL2 (Y13A S21K Q23R), embodying increased affinity for GAGs as well as knocked-out GPCR activation properties. This non-signalling dominant-negative mutant is shown here to be able to displace wild type CCL2 from GAGs by which it is supposed to interfere with the chemokine-related inflammatory response. In vivo, the anti-inflammatory properties were successfully demonstrated in a murine model of zymosan-induced peritonitis as well as in an experimental autoimmune encephalomyelitis, a model relevant for multiple sclerosis, where the compound lead to significantly reduced clinical scores due to reduction of cellular infiltrates and demyelination in spinal cord and cerebellum. These findings indicate a promising potential for future therapeutic development.

Journal Article Type Article
Acceptance Date May 18, 2016
Online Publication Date May 19, 2016
Publication Date Jul 28, 2016
Deposit Date Sep 27, 2017
Publicly Available Date Sep 27, 2017
Journal Neuroscience Letters
Print ISSN 0304-3940
Electronic ISSN 1872-7972
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 626
Pages 164-173
DOI https://doi.org/10.1016/j.neulet.2016.05.037
Keywords CCL2 decoy, Glycosaminoglycans, Anti-inflammatory, Multiple sclerosis, Experimental autoimmune encephalomyelitis
Public URL https://nottingham-repository.worktribe.com/output/798633
Publisher URL http://www.sciencedirect.com/science/article/pii/S0304394016303494

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