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

Journal article

Multiple Sclerosis, a chronic inflammatory demyelinating disease of the central nervous system, involves 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.

Authors: Gschwandtner, M; Piccinini, A; Gerlza, T; Adage, T; Kungl, A

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Elsevier
• Journal: Neuroscience Letters
• Volume: 626
• Pages: 164-173
• Publication date: 2016-05-19
• Acceptance date: 2016-05-18
• DOI: 10.1016/j.neulet.2016.05.037
• EISSN: 1872-7972
• ISSN: 0304-3940
• Pmid: 27212623
• Language: English
• Keywords: anti-inflammatory agents; anti-inflammatory; monocytes; dexamethasone; mice, inbred C57BL; male; peritonitis; disease models, animal; cerebellum; experimental autoimmune encephalomyelitis; mice; myelin-oligodendrocyte glycoprotein; encephalitis; Multiple Sclerosis; spinal cord; inhibitory concentration 50; peptide fragments; animals; female; zymosan; chemokine CCL2; glycosaminoglycans; encephalomyelitis, autoimmune, experimental; CCL2 decoy