myelin-oligodendrocyte-glycoprotein-(35-55) and Peritonitis

Macrophages are highly plastic, key regulators of inflammation. Deregulation of macrophage activation can lead to excessive inflammation as seen in inflammatory disorders like atherosclerosis, obesity, multiple sclerosis and sepsis. Targeting intracellular metabolism is considered as an approach to reshape deranged macrophage activation and to dampen the progression of inflammatory disorders. ATP citrate lyase (Acly) is a key metabolic enzyme and an important regulator of macrophage activation. Using a macrophage-specific Acly-deficient mouse model, we investigated the role of Acly in macrophages during acute and chronic inflammatory disorders. First, we performed RNA sequencing to demonstrate that Acly-deficient macrophages showed hyperinflammatory gene signatures in response to acute LPS stimulation

Topics: Animals; ATP Citrate (pro-S)-Lyase; Cells, Cultured; Cytokines; Diet, High-Fat; Encephalomyelitis, Autoimmune, Experimental; Inflammation; Inflammation Mediators; Lipopolysaccharides; Macrophages; Mice, Inbred C57BL; Mice, Knockout; Myelin-Oligodendrocyte Glycoprotein; Obesity; Peptide Fragments; Peritonitis; Phenotype; Signal Transduction

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.

Topics: 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