Chemokines induce eosinophil degranulation through CCR-3

Background: Such CC chemokines as eotaxin and RANTES induce preferential eo sinophil recruitment in allergic inflammation. They also elicit proinflamma tory effector functions of eosinophils, such as enhanced adhesion and super oxide generation. Eosinophil degranulation by chemokines, however, has not been studied in detail. Objective: The purpose of this study was to identify chemokines and their c orresponding receptors that induce eosinophil degranulation by using a pane l of chemokines and blocking antibodies to candidate receptors. Methods: Highly purified eosinophils were preloaded with Fura-2 and stimula ted with a panel of chemokine ligands for 14 known chemokine receptors: CCR 1 to CCR8, CXCR1 to CXCR4 CX3CR1, and XCR1. Calcium influx was measured wit h fluorescence spectrometry. Eosinophils were also stimulated with the chem okines in the presence or absence of IL-5, and levels of eosinophil-derived neurotoxin were measured in the supernatant with RIA. Specific antibodies to chemokine receptors were used to block degranulation. Results: Calcium influx was induced by monocyte chemotactic protein (MCP) 1 , MCP3, MCP-4, RANTES, eotaxin, IL-8, and stromal cell-derived factor 1 alp ha, which are chemokines that bind several chemokine receptors. However, de granulation was induced only by CCR3 ligands, including MCP3, MCP-4, RANTES , and eotaxin. Priming of eosinophils with IL-5 enhanced CCR3 ligand-induce d degranulation but did not cause non-CCR3 ligands to induce eosinophil-der ived neurotoxin release. An antibody against CCR3 significantly inhibited d egranulation induced by CCR3 ligands, eotaxin, or RANTES. Conclusion: These results suggest that chemokine-induced eosinophil degranu lation, a major effector of eosinophil functions, is mediated through only CCR3, although some non-CCR3 ligands induce calcium influx in eosinophils. CCR3 may be an important target in the treatment of eosinophilic inflammati on.