Synthetic chemerin-derived peptides suppress inflammation through ChemR23.

Abstract

Chemerin is a chemotactic protein that binds to the G protein-coupled receptor, ChemR23. We demonstrate that murine chemerin possesses potent antiinflammatory properties that are absolutely dependent on proteolytic processing. A series of peptides was designed, and only those identical to specific C-terminal chemerin sequences exerted antiinflammatory effects at picomolar concentrations in vitro. One of these, chemerin15 (C15; A(140)-A(154)), inhibited macrophage (MPhi) activation to a similar extent as proteolyzed chemerin, but exhibited reduced activity as a MPhi chemoattractant. Intraperitoneal administration of C15 (0.32 ng/kg) to mice before zymosan challenge conferred significant protection against zymosan-induced peritonitis, suppressing neutrophil (63%) and monocyte (62%) recruitment with a concomitant reduction in proinflammatory mediator expression. Importantly, C15 was unable to ameliorate zymosan-induced peritonitis in ChemR23(-/-) mice, demonstrating that C15's antiinflammatory effects are entirely ChemR23 dependent. In addition, administration of neutralizing anti-chemerin antibody before zymosan challenge resulted in a significant exacerbation of peritoneal inflammation (up to 170%), suggesting an important endogenous antiinflammatory role for chemerin-derived species. Collectively, these results show that chemerin-derived peptides may represent a novel therapeutic strategy for the treatment of inflammatory diseases through ChemR23.

• Authors: Jenna L Cash, Rosie Hart, Andreas Russ, John P C Dixon, William H Colledge, Joanne Doran, Alan G Hendrick, Mark B L Carlton, David R Greaves
• Journal: The Journal of experimental medicine (J Exp Med) Vol. 205 Issue 4 Pg. 767-75 (Apr 14 2008) ISSN: 1540-9538 [Electronic] United States
• PMID: 18391062 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Inflammatory Agents
• Antibodies
• CMKLR1 protein, mouse
• Chemokines
• Chemotactic Factors
• Intercellular Signaling Peptides and Proteins
• Peptides
• Receptors, Chemokine
• Receptors, G-Protein-Coupled
• chemerin protein, mouse
• Zymosan

Topics

• Animals
• Anti-Inflammatory Agents (pharmacology)
• Antibodies (pharmacology)
• Chemokines
• Chemotactic Factors (pharmacology, therapeutic use)
• Chemotaxis (drug effects)
• Inflammation (drug therapy, pathology)
• Intercellular Signaling Peptides and Proteins (pharmacology, therapeutic use)
• Macrophage Activation (drug effects)
• Macrophages, Peritoneal (cytology, drug effects)
• Mice
• Mice, Inbred C57BL
• Neutralization Tests
• Peptides (pharmacology)
• Peritonitis (pathology)
• Protein Processing, Post-Translational (drug effects)
• Receptors, Chemokine
• Receptors, G-Protein-Coupled (deficiency, metabolism)
• Zymosan