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

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

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.

Citation

Gschwandtner, M., Piccinini, A. M., Geriza, T., Adage, T., & Kungl, A. (2016). Interfering with the CCL2-glycosaminoglycan axis as a potential approach to modulate neuroinflammation. Neuroscience Letters, 626, 164-173. https://doi.org/10.1016/j.neulet.2016.05.037

• 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
• Contract Date: Sep 27, 2017