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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

Authors

Martha Gschwandtner

Anna Maria Piccinini

Tanja Geriza

Tiziana Adage

Andreas Kungl



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.

Journal Article Type Article
Publication Date Jul 28, 2016
Journal Neuroscience Letters
Print ISSN 0304-3940
Electronic ISSN 1872-7972
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 626
APA6 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, doi:10.1016/j.neulet.2016.05.037
DOI https://doi.org/10.1016/j.neulet.2016.05.037
Keywords CCL2 decoy, Glycosaminoglycans, Anti-inflammatory, Multiple sclerosis, Experimental autoimmune encephalomyelitis
Publisher URL http://www.sciencedirect.com/science/article/pii/S0304394016303494
Copyright Statement Copyright information regarding this work can be found at the following address: http://eprints.nottingh.../end_user_agreement.pdf

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Copyright Statement
Copyright information regarding this work can be found at the following address: http://eprints.nottingham.ac.uk/end_user_agreement.pdf





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