title: Interfering with the CCL2-glycosaminoglycan axis as a potential approach to modulate neuroinflammation.
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.
authors.affiliation: Institute of Pharmaceutical Sciences, University of Graz, Schubertstraße 1/1, A- 8010 Graz, Austria.
authors.forename: Martha
authors.initials: M
authors.lastname: Gschwandtner
authors.affiliation: ProtAffin Biotechnologie AG, A- 8020 Graz, Austria.
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Piccinini
authors.affiliation: ProtAffin Biotechnologie AG, A- 8020 Graz, Austria.
authors.forename: Tanja
authors.initials: T
authors.lastname: Gerlza
authors.affiliation: ProtAffin Biotechnologie AG, A- 8020 Graz, Austria.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Adage
authors.affiliation: Institute of Pharmaceutical Sciences, University of Graz, Schubertstraße 1/1, A- 8010 Graz, Austria; ProtAffin Biotechnologie AG, A- 8020 Graz, Austria. Electronic address: andreas.kungl@uni-graz.at.
authors.forename: Andreas J
authors.initials: AJ
authors.lastname: Kungl
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D002531:Cerebellum / Q000187:drug effects / Q000473:pathology; D018932:Chemokine CCL2 / Q000008:administration & dosage* / Q000235:genetics / Q000493:pharmacokinetics; D003907:Dexamethasone / Q000008:administration & dosage; D004195:Disease Models, Animal; D004660:Encephalitis / Q000517:prevention & control*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000517:prevention & control; D005260:Female; D006025:Glycosaminoglycans / Q000737:chemistry*; D020128:Inhibitory Concentration 50; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000187:drug effects; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; D010538:Peritonitis / Q000139:chemically induced / Q000517:prevention & control; D013116:Spinal Cord / Q000187:drug effects / Q000473:pathology; D015054:Zymosan
chemical_list: D000893:Anti-Inflammatory Agents; C111835:CCL2 protein, human; D018932:Chemokine CCL2; D006025:Glycosaminoglycans; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; C445081:myelin oligodendrocyte glycoprotein (35-55); D003907:Dexamethasone; D015054:Zymosan
keywords: Anti-inflammatory; CCL2 decoy; Experimental autoimmune encephalomyelitis; Glycosaminoglycans; Multiple sclerosis