کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
4343196 | 1615073 | 2016 | 10 صفحه PDF | دانلود رایگان |
![عکس صفحه اول مقاله: Interfering with the CCL2–glycosaminoglycan axis as a potential approach to modulate neuroinflammation Interfering with the CCL2–glycosaminoglycan axis as a potential approach to modulate neuroinflammation](/preview/png/4343196.png)
• 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.
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.
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Journal: Neuroscience Letters - Volume 626, 28 July 2016, Pages 164–173