Chemerin Peptides Promote Phagocytosis in

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 (MF) phagocytosis of microbial particles and apoptotic cells by up to 360% in vitro. These prophagocytic effects of C15 are significantly impaired in ChemR23 2/2 MFs 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 MFs in wild-type but not ChemR23 2/2 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 MF 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. M acrophages (MFs) are innate immune cells that can recognize, phagocytose, and kill microbial pathogens; as such, they represent an important component of the body's defense against infection (1–3). Efficient clearance of pathogenic material by MFs is important in limiting the magnitude and duration of the ensuing inflammatory response, although recognition and engulfment of microbial particles by MFs typically results in their activation and the secretion of inflammatory cytokines (4, 5). In contrast, MF ingestion of apoptotic cells is nonphlogistic (noninflammatory) because it does not provoke in-flammatory mediator expression and is associated with active suppression of proinflammatory mediator release and upregulation of anti-inflammatory mediator expression, including TGF-b (6–9). Thus, apoptotic cell phagocytosis (efferocytosis) plays an important role in the resolution of inflammation and the maintenance of peripheral immune tolerance (1, 2, 7, 9, 10). Inefficient clearance of apoptotic cells, resulting in the accumulation of secondary necrotic cells, can …