The Journal of Experimental Medicine
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Published online April 7, 2008
doi:10.1084/jem.20071601
The Journal of Experimental Medicine, Vol. 205, No. 4, 767-775
The Rockefeller University Press, 0022-1007 $30.00
© 2008 Cash et al.
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BRIEF DEFINITIVE REPORT

 Synthetic chemerin-derived peptides suppress inflammation through ChemR23

Jenna L. Cash1, Rosie Hart1, Andreas Russ2, John P.C. Dixon3, William H. Colledge3, Joanne Doran3, Alan G. Hendrick3, Mark B.L. Carlton3, and David R. Greaves1

1 Sir William Dunn School of Pathology and 2 Department of Biochemistry, University of Oxford, Oxford OX1 3RE, England, UK
3 Takeda Cambridge, Cambridge CB4 OPA, England, UK

CORRESPONDENCE David R. Greaves: david.greaves{at}path.ox.ac.uk

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; A140-A154), inhibited macrophage (M{Phi}) activation to a similar extent as proteolyzed chemerin, but exhibited reduced activity as a M{Phi} 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.


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