A novel inflammatory pathway involved in leukocyte recruitment: role for the kinin B1 receptor and the chemokine CXCL5.
The kinin B1 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-1beta. 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-1beta-induced leukocyte rolling, adherence, and emigration in mesenteric venules of wild-type (WT) mice, associated with an increase in B1 receptor mRNA expression, were substantially attenuated (>80%) in B1 receptor knockout mice (B1KO). This effect in B1KO mice was correlated with a selective down-regulation of IL-1beta-induced CXCL5 mRNA and protein expression compared with WT mice. Furthermore a selective neutralizing CXCL5 Ab caused profound suppression of leukocyte emigration in IL-1beta-treated WT mice. Finally, treatment of human endothelial cells with IL-1beta enhanced mRNA expression of the B1 receptor and the human (h) CXCL5 homologues (hCXCL5 and hCXCL6). This response was suppressed by approximately 50% when cells were pretreated with the B1 receptor antagonist des-Arg9-[Leu8]-bradykinin while treatment with des-Arg9-bradykinin, the B1 receptor agonist, caused a concentration-dependent increase in hCXCL5 and hCXCL6 mRNA expression. This study unveils a proinflammatory pathway centered on kinin B1 receptor activation of CXCL5 leading to leukocyte trafficking and highlights the B1 receptor as a potential target in the therapeutics of inflammatory disease.
Duchene
Johan
J
William Harvey Research Institute, St. Barts and the London Medical School, Charterhouse Square, London, United Kingdom.
Lecomte
Florence
F
Ahmed
Saleh
S
Cayla
Cecile
C
Pesquero
Joao
J
Bader
Michael
M
Perretti
Mauro
M
Ahluwalia
Amrita
A
D000818:Animals; D002448:Cell Adhesion; D002465:Cell Movement; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism; D005786:Gene Expression Regulation; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D007962:Leukocytes / Q000166:cytology* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D043783:Receptor, Bradykinin B1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D054380:Receptors, CXCR5; D019707:Receptors, Chemokine / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
C095085:CXCR5 protein, human; C513179:CXCR5 protein, mouse; D043783:Receptor, Bradykinin B1; D054380:Receptors, CXCR5; D019707:Receptors, Chemokine