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

Gschwandtner, Martha and Piccinini, Anna Maria and Geriza, Tanja and Adage, Tiziana and Kungl, Andreas (2016) Interfering with the CCL2–glycosaminoglycan axis as a potential approach to modulate neuroinflammation. Neuroscience Letters, 626 . pp. 164-173. ISSN 1872-7972

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Abstract

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 (Y13AS21K 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.

Item Type: Article
Keywords: CCL2 decoy, Glycosaminoglycans, Anti-inflammatory, Multiple sclerosis, Experimental autoimmune encephalomyelitis
Schools/Departments: University of Nottingham, UK > Faculty of Science > School of Pharmacy
Identification Number: 10.1016/j.neulet.2016.05.037
Depositing User: Eprints, Support
Date Deposited: 27 Sep 2017 08:02
Last Modified: 14 Oct 2017 08:36
URI: http://eprints.nottingham.ac.uk/id/eprint/46751

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