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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.

Original publication

DOI

10.1016/j.neulet.2016.05.037

Type

Journal article

Journal

Neurosci Lett

Publication Date

28/07/2016

Volume

626

Pages

164 - 173

Keywords

Anti-inflammatory, CCL2 decoy, Experimental autoimmune encephalomyelitis, Glycosaminoglycans, Multiple sclerosis, Animals, Anti-Inflammatory Agents, Cerebellum, Chemokine CCL2, Dexamethasone, Disease Models, Animal, Encephalitis, Encephalomyelitis, Autoimmune, Experimental, Female, Glycosaminoglycans, Inhibitory Concentration 50, Male, Mice, Mice, Inbred C57BL, Monocytes, Myelin-Oligodendrocyte Glycoprotein, Peptide Fragments, Peritonitis, Spinal Cord, Zymosan