Synthetic chemerin-derived peptides suppress inflammation through ChemR23.
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.
Cash
Jenna L
JL
Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, England, UK.
Hart
Rosie
R
Russ
Andreas
A
Dixon
John P C
JP
Colledge
William H
WH
Doran
Joanne
J
Hendrick
Alan G
AG
Carlton
Mark B L
MB
Greaves
David R
DR
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D000906:Antibodies / Q000494:pharmacology; D018925:Chemokines; D002630:Chemotactic Factors / Q000494:pharmacology* / Q000627:therapeutic use; D002633:Chemotaxis / Q000187:drug effects; D007249:Inflammation / Q000188:drug therapy / Q000473:pathology*; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology* / Q000627:therapeutic use; D008262:Macrophage Activation / Q000187:drug effects; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009500:Neutralization Tests; D010455:Peptides / Q000494:pharmacology*; D010538:Peritonitis / Q000473:pathology; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D019707:Receptors, Chemokine; D043562:Receptors, G-Protein-Coupled / Q000172:deficiency / Q000378:metabolism*; D015054:Zymosan
D000893:Anti-Inflammatory Agents; D000906:Antibodies; C486456:CMKLR1 protein, mouse; D018925:Chemokines; D002630:Chemotactic Factors; D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; D019707:Receptors, Chemokine; D043562:Receptors, G-Protein-Coupled; C523686:chemerin protein, mouse; D015054:Zymosan