Chemokines synergize in the recruitment of circulating neutrophils into inflamed tissue.

The innate immune response against micro-organisms is mediated by phagocytes, attracted by chemokines and other G protein-coupled receptor (GPCR) ligands. Originally, we observed increased neutrophil migration by the interaction of inflammatory CXC chemokines such as IL-8/CXCL8 and granulocyte chemotactic protein (GCP)-2/CXCL6 with regakine-1, a CC chemokine constitutively present in plasma. We here demonstrate statistically significant synergy between regakine-1 and the neutrophil attractants C5a or IL-8/CXCL8 in inducing neutrophil shape change and migration under agarose. In addition, regakine-1 attracted human bone marrow granulocytes and enhanced their chemotactic response to IL-8/CXCL8 in a dose-dependent manner. Thus, plasma chemokines may regulate the number of circulating leukocytes under homeostatic conditions and may facilitate extra recruitment of bone marrow neutrophils during inflammation. Indeed, in vivo, regakine-1 provoked a mild neutrophilia in rabbits upon intravenous injection. We also observed that the CC chemokines regakine-1 and monocyte chemotactic protein-3/CCL7 as well as the CXC chemokine stromal cell-derived factor-1alpha/CXCL12 co-operated with murine GCP-2 after intraperitoneal co-administration to increase neutrophil influx in mice. These data demonstrate that inducible and constitutive GPCR ligands synergize to enhance inflammation and facilitate a more effective immune response.