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

Differential Patterns of Serum Concentration and Adipose Tissue Expression of Chemerin in Obesity: Adipose Depot Specificity and Gender Dimorphism

“…These conflicting results can potentially be explained by the presence of multiple chemerin-derived peptides. Whereas peptides derived from cleavage of the biologically inactive pro-chemerin by serine proteases exert chemotactic/proinflammatory activity (Wittamer et al, 2005), cysteine protease-derived peptides have anti-inflammatory effects (Cash et al, 2008). In the present study, results from the ELISA assay revealed a positive association between the circulating levels of chemerin and leptin; however, the same was not true for chemerin mRNA expression levels in adipose tissue (both subcutaneous and visceral) and circulating leptin.…”

“…Although most of the published data support a proinflammatory role for chemerin Kralisch et al, 2009;Parlee et al, 2010), some studies have related chemerin expression to anti-inflammatory actions (Cash et al, 2008;Luangsay et al, 2009). These conflicting results can potentially be explained by the presence of multiple chemerin-derived peptides.…”

“…Chemerin, a recently discovered circulating chemokine, exerts its actions through cell surface receptors termed chemokine-like receptor 1 (CMKLR1), G protein-coupled receptor 1 (GPR1), or chemokine (C-C motif) receptor-like 2 (CCRL2) (Barnea et al, 2008;Cash et al, 2008;Wittamer et al, 2003;Zabel et al, 2008). Later studies characterized chemerin as an adipokine with a potential role in regulating adipocyte development in vitro and metabolic functions, such as glucose and lipid metabolism, in adipose tissue (Goralski et al, 2007).…”

Trafficking properties of plasmacytoid dendritic cells in health and disease

“…The anti-inflammatory lipid Resolvin E1 was shown to exert its function through interaction with ChemR23. In addition, chemerin proteolytically generated peptides possess anti-inflammatory activity in vivo [94,95]. Therefore, ChemR23 may also possess anti-inflammatory activities, as recently suggested in experiments testing a mouse model of lung inflammation [96].…”

Characterization and functional study of a cluster of four highly conserved orphan adhesion‐GPCR in mouse

“…The 5 0 and 3 0 flanking arms were amplified using genomic DNA from 129Sv/Ev mice. The vector for homologous recombination was constructed as described previously (Russ et al, 2000;Cash et al, 2008). Briefly, targeting constructs were created by inserting 5 0 arms upstream of the lacZ-Neo cassette, and 3 0 arms between the lacZ-Neo cassette and a thymidine kinase gene.…”