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Receptor and the Chemokine CXCL5 1 A Novel Inflammatory Pathway Involved in Leukocyte Recruitment: Role for the Kinin B 1 Receptor and the Chemokine CXCL5 This information is current as Johan Duchene, Florence Lecomte, Saleh Ahmed, Cecile of September 27, 2021. Cayla, Joao Pesquero, Michael Bader, Mauro Perretti and Amrita Ahluwalia J Immunol 2007; 179:4849-4856; ; doi: 10.4049/jimmunol.179.7.4849 http://www.jimmunol.org/content/179/7/4849 Downloaded from References This article cites 51 articles, 18 of which you can access for free at: http://www.jimmunol.org/content/179/7/4849.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 27, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2007 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology 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 Ahluwalia2* 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 Downloaded from 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 ϳ50% when cells were pretreated with 9 8 9 the B1 receptor antagonist des-Arg -[Leu ]-bradykinin while treatment with des-Arg -bradykinin, the B1 receptor agonist, caused http://www.jimmunol.org/ 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 Journal of Immunology, 2007, 179: 4849–4856. eukocyte recruitment at sites of tissue injury is an impor- kinins are brought about by their interaction with specific G pro- tant facet of an inflammatory response (1). Polymorpho- tein-coupled receptors. At present, there are two clearly defined nuclear neutrophils (PMNs)3 are the first cells recruited to and cloned kinin receptors: B and B . The B receptor, which is L 1 2 2 the inflammatory site and their uncontrolled accumulation is activated by BK, is constitutively expressed, suffers rapid desen- by guest on September 27, 2021 thought to contribute to organ dysfunction (2). One of the integral sitization following activation, and mediates many of the acute cytokines involved in cell recruitment is IL-1␤ (3). IL-1␤ brings actions of the kinins including edema, increased blood flow, and about its effects by activating a number of proinflammatory path- pain (6–8). In contrast the B1 receptor, activated by DABK, is ways. In particular, this cytokine induces the expression of several normally absent but is induced under inflammatory conditions, of- acute response proteins, one of which is the kinin B1 receptor. Our ten hand-in-hand with an enhancement of the circulating levels of previous work demonstrates that this receptor plays an important the endogenous B agonist, DABK, and does not undergo desen- ␤ 1 role in mediating IL-1 -induced leukocyte recruitment (4, 5). sitization upon activation (6–8). This receptor is induced during The kinins are commonly recognized as a family of inflamma- inflammation by certain immunostimulants, the optimal inducer tory peptides (6–8), the effects of which are mediated by the en- being IL-1␤ (5, 7–9). In addition to a number of the inflammatory dogenous agonists bradykinin (BK) and one of the main metabo- 9 functions exhibited by B2 receptor activation (6–8), B1 receptor lites of BK, des-Arg -BK (DABK). The biological effects of the activation also stimulates leukocyte recruitment by promoting in- teraction between leukocytes and the endothelium, resulting in increased rolling, adhesion, and migration of PMNs (4, 5). Signif- *William Harvey Research Institute, St. Barts and the London Medical School, Char- † ␤ terhouse Square, London, United Kingdom; Escola Paulista de Medicina, Univer- icantly, antagonism of B1 receptors in vivo attenuates IL-1 -in- sidade Federal de Sao Paulo, Sao Paulo, Brazil; and ‡Max-Delbru¨ck-Center for Mo- duced leukocyte accumulation (5), and inflammatory responses de- lecular Medicine Berlin-Buch, Berlin, Germany pendent upon leukocyte recruitment are attenuated in kinin B1 Received for publication January 5, 2007. Accepted for publication July 19, 2007. receptor knockout (B1KO) mice (10); however, the exact down- The costs of publication of this article were defrayed in part by the payment of page stream mechanisms involved in this response have yet to be charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. determined. 1 This work was supported by the Fondation pour la Recherche Medicale and the Chemokines are proinflammatory cytokines that stimulate leu- British Heart Foundation (to J.D.). F.L. was supported by The Wellcome Trust. kocyte chemoattraction and are produced in response to infectious 2 Address correspondence and reprint requests to Dr. Amrita Ahluwalia, Clinical and other inflammatory stimuli by a number of different cell types, Pharmacology, William Harvey Research Institute, Saint Barts and the London Med- ical School, Charterhouse Square, London EC1M 6BQ, United Kingdom. E-mail including endothelial cells (11). That endothelial cells produce address: [email protected] chemokines is of particular significance because within the vascu- 3 Abbreviations used in this paper: PMN, polymorphonuclear neutrophil; BK, brady- lature the endothelial cell is the site for leukocyte recruitment, and 9 kinin; B1KO, B1 receptor knockout; DABK, des-Arg -BK; h, human; MPO, myelo- expression of chemokines on the endothelial cell surface plays a peroxidase; WT, wild type. pivotal role in leukocyte migration by facilitating the direct inter- Copyright © 2007 by The American Association of Immunologists, Inc. 0022-1767/07/$2.00 action of endothelial cells with leukocytes (1). More than 50 www.jimmunol.org 4850 KININ B1 RECEPTOR INDUCES CXCL5 chemokines have been identified to date and have been classified determination of MPO levels as previously described (15). Data are expressed into four groups according to the location of the conserved cys- as units per gram of total protein content in the tissue as determined by Brad- teine residues: CXCL, CCL, CL, and CX3CL (12). These chemo- ford assay. kines play differential roles in specifically recruiting different cell Real-time quantitative RT-PCR of murine mesenteric tissue types to an inflammatory site. With respect to neutrophil recruit- Chemokine mRNA expression was determined by real-time quantitative ment, the presence of a trio of amino acids, glutamate-leucine- RT-PCR. Briefly, mesenteric tissue was removed from saline or IL-1␤- arginine (ELR), before the CXCL motif appears to confer selec- treated (for 2 h) mice as described above, snap frozen in liquid nitrogen, tivity for promoting neutrophil migration (13). The most well and stored at Ϫ80°C until use. Samples were homogenized and total RNA described ELR-CXCL chemokines in mice include CXCL1 (also was isolated using a NucleoSpin RNA II purification kit (Macherey-Nagel) and then stored at Ϫ80°C until use. cDNA was synthesized from 1 ␮gof called keratinocyte-derived chemokine or KC), CXCL2 (also total RNA with Moloney murine leukemia virus reverse transcriptase (Pro- called macrophage inflammation protein-2 or MIP-2), CXCL5 mega) using oligo(dT) nucleotides. The following primers were used for (also called LPS-inducible CXC chemokine or LIX), and CXCL7 mouse: CXCL1, 5Ј-TGAGCTGCGCTGTCAGTGCCT-3Ј and 5Ј-AGAA (also called neutrophil activating peptide-2 or NAP-2). Although GCCAGCGTTCACCAGA-3Ј; CXCL2, 5Ј-GAGCTTGAGTGTGACGCC Ј Ј Ј good evidence
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