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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.

Original publication

DOI

10.1084/jem.20071601

Type

Journal article

Journal

J Exp Med

Publication Date

14/04/2008

Volume

205

Pages

767 - 775

Keywords

Animals, Anti-Inflammatory Agents, Antibodies, Chemokines, Chemotactic Factors, Chemotaxis, Inflammation, Intercellular Signaling Peptides and Proteins, Macrophage Activation, Macrophages, Peritoneal, Mice, Mice, Inbred C57BL, Neutralization Tests, Peptides, Peritonitis, Protein Processing, Post-Translational, Receptors, G-Protein-Coupled, Zymosan