A novel inflammatory pathway recruitment: Role for the kinin chemokine CXCL5

The kinin B-1 receptor is an inducible receptor not normally expressed but induced by inflammatory stimuli and plays a major role in neutrophil recruitment, particularly in response to the cytokine IL-1 beta. However, the exact mechanism involved in this response is unclear. The aim of this study was to dissect the molecular mechanism involved, in particular to determine whether specific ELR-CXCL chemokines (specific neutrophil chemoattractants) played a role. Using intravital microscopy, we demonstrated that IL-1 beta-induced leukocyte rolling, adherence, and emigration in mesenteric venules of wild-type (WT) mice, associated with an increase in B, receptor mRNA expression, were substantially attenuated (>80%) in B, receptor knockout mice (B1KO). This effect in B1KO mice was correlated with a selective down-regulation of IL-1 beta-induced CXCL5 mRNA and protein expression compared with WT mice. Furthermore a selective neutralizing CXCL5 Ab caused profound suppression of leukocyte emigration in IL-1 beta-treated WT mice. Finally, treatment of human endothelial cells with IL-1 beta enhanced mRNA expression of the B, receptor and the human (h) CXCL5 homologues (hCXCL5 and hCXCL6). This response was suppressed by similar to 50% when cells were pretreated with the B, receptor antagonist des-Arg(9)-[Leu(8)]-bradykinin while treatment with des-Arg(9)-bradykinin, the B-1 receptor agonist, caused a concentration-dependent increase in hCXCL5 and hCXCL6 mRNA expression. This study unveils a proinflammatory pathway centered on kinin B-1 receptor activation of CXCL5 leading to leukocyte trafficking and highlights the B-1 receptor as a potential target in the therapeutics of inflammatory disease.