title: Chemerin peptides promote phagocytosis in a ChemR23- and Syk-dependent manner.
abstract: Chemerin peptides represent a recently identified component of the endogenous anti-inflammatory network that act via the G protein-coupled receptor ChemR23. The role of the chemerin peptide/ChemR23 pathway in phagocytosis, the clearance of apoptotic cells (efferocytosis), and the resolution of inflammation is unknown. In this article, we report that low picomolar concentrations of the chemerin peptide chemerin15 (C15) enhance macrophage (MPhi) phagocytosis of microbial particles and apoptotic cells by up to 360% in vitro. These prophagocytic effects of C15 are significantly impaired in ChemR23(-/-) MPhis and are associated with increased actin polymerization and localization of F-actin to the phagocytic cup. Importantly, pharmacological inhibition of Syk activity completely abrogates the prophagocytic activities of C15 and associated changes in actin polymerization and phagocytic cup formation, suggesting that C15 promotes phagocytosis by facilitating phagocytic cup development in a Syk-dependent manner. During peritoneal inflammation, C15 administration (8 pg/mouse) enhances microbial particle clearance and apoptotic neutrophil ingestion by MPhis in wild-type but not ChemR23(-/-) mice, such that levels of apoptotic and necrotic cells at the inflammatory site are profoundly reduced. In contrast, neutralization of endogenous chemerin species during peritoneal inflammation significantly impairs MPhi ingestion of apoptotic neutrophils and zymosan. Our data identify a key role of the chemerin peptide/ChemR23 axis in the efficient clearance of foreign material, efferocytosis, and, hence, the resolution of inflammation. Manipulation of the chemerin peptide/ChemR23 axis may represent a novel therapeutic approach for the treatment of inflammatory pathologies, especially if failure to efficiently clear phagocytic targets has been implicated in their pathogenesis.
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom.
authors.forename: Jenna L
authors.initials: JL
authors.lastname: Cash
authors.forename: Annabel R
authors.initials: AR
authors.lastname: Christian
authors.forename: David R
authors.initials: DR
authors.lastname: Greaves
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000276:immunology; D002478:Cells, Cultured; D018925:Chemokines; D002630:Chemotactic Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D019169:Jurkat Cells; D008024:Ligands; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D010446:Peptide Fragments / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D010455:Peptides / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D010587:Phagocytosis / Q000276:immunology*; D010588:Phagosomes / Q000201:enzymology / Q000276:immunology; D010641:Phenotype; D011505:Protein-Tyrosine Kinases / Q000502:physiology*; D019707:Receptors, Chemokine; D043562:Receptors, G-Protein-Coupled / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000072377:Syk Kinase
chemical_list: C486456:CMKLR1 protein, mouse; D018925:Chemokines; D002630:Chemotactic Factors; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D010446:Peptide Fragments; D010455:Peptides; D019707:Receptors, Chemokine; D043562:Receptors, G-Protein-Coupled; C523686:chemerin protein, mouse; C000589458:chemerin15 peptide, mouse; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse