Interfering with the CCL2–glycosaminoglycan axis as a potential approach to modulate neuroinflammation. (28th July 2016)

• Record Type: Journal Article
• Authors: Gschwandtner, Martha; Piccinini, Anna Maria; Gerlza, Tanja; Adage, Tiziana; Kungl, Andreas J.
• Is Part Of: Neuroscience letters. Volume 626(2016)
• Page Start: 164
• Page End: 173
• Publication Date: 2016-07-28
• Subjects: MCP-1/CCL2 monocyte chemoattractant protein-1/ -- GPCR G-protein coupled receptor -- GAG glycosaminoglycan ECM extracellular matrix -- EAE experimental autoimmune encephalomyelitis -- MS multiple sclerosis -- CNS central nervous system -- MOG myelin-oligodendrocyte-glycoprotein; CCL2 decoy -- Glycosaminoglycans -- Anti-inflammatory -- Multiple sclerosis -- Experimental autoimmune encephalomyelitis; Neurology -- Periodicals; Neurology -- Periodicals; Research -- Periodicals; Neurologie -- Périodiques; Neuroanatomie -- Périodiques; Neuropharmacologie -- Périodiques; Neurophysiologie -- Périodiques; Neurology; Periodicals; Electronic journals; 617.48
• DOI: 10.1016/j.neulet.2016.05.037
• Languages: English
• ISSNs: 0304-3940

Abstract

Graphical abstract: Highlights: CCL2 decoy with enhanced GAG binding properties and knocked-out GPCR activation. Decoy shows anti-migratory activity towards inflammatory monocytes and therefore anti-inflammatory properties. Ameliorating effect was shown in an experimental autoimmune encephalitis, a model of Multiple Sclerosis. 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 (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.