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A Novel Inflammatory Pathway Involved in Leukocyte Recruitment: Role for the Kinin B₁ Receptor and the Chemokine CXCL5¹

Johan Duchene^*, Florence Lecomte^*, Saleh Ahmed^*, Cecile Cayla^*, Joao Pesquero, Michael Bader, Mauro Perretti^* and Amrita Ahluwalia^2,*

^* William Harvey Research Institute, St. Barts and the London Medical School, Charterhouse Square, London, United Kingdom; Escola Paulista de Medicina, Universidade Federal de Sao Paulo, Sao Paulo, Brazil; and Max-Delbrück-Center for Molecular Medicine Berlin-Buch, Berlin, Germany

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-1. 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-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-1-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-treated WT mice. Finally, treatment of human endothelial cells with IL-1 enhanced mRNA expression of the B₁ receptor and the human (h) CXCL5 homologues (hCXCL5 and hCXCL6). This response was suppressed by 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Fondation pour la Recherche Medicale and the British Heart Foundation (to J.D.). F.L. was supported by The Wellcome Trust.

² Address correspondence and reprint requests to Dr. Amrita Ahluwalia, Clinical Pharmacology, William Harvey Research Institute, Saint Barts and the London Medical School, Charterhouse Square, London EC1M 6BQ, United Kingdom. E-mail address: a.ahluwalia{at}qmul.ac.uk

³ Abbreviations used in this paper: PMN, polymorphonuclear neutrophil; BK, bradykinin; B1KO, B₁ receptor knockout; DABK, des-Arg⁹-BK; h, human; MPO, myeloperoxidase; WT, wild type.