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Of VLA-4 and VLA-5 VCAM-1 and Fibronectin Through Clustering Promoting Macrophage Adhesion to Chemerin Contributes to Inflammati

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Of VLA-4 and VLA-5 VCAM-1 and Fibronectin Through Clustering Promoting Macrophage Adhesion to Chemerin Contributes to Inflammati Chemerin Contributes to Inflammation by Promoting Macrophage Adhesion to VCAM-1 and Fibronectin through Clustering of VLA-4 and VLA-5 This information is current as of October 1, 2021. Rosie Hart and David R. Greaves J Immunol 2010; 185:3728-3739; Prepublished online 18 August 2010; doi: 10.4049/jimmunol.0902154 http://www.jimmunol.org/content/185/6/3728 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2010/08/18/jimmunol.090215 Material 4.DC1 http://www.jimmunol.org/ References This article cites 60 articles, 30 of which you can access for free at: http://www.jimmunol.org/content/185/6/3728.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on October 1, 2021 • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *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 © 2010 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Chemerin Contributes to Inflammation by Promoting Macrophage Adhesion to VCAM-1 and Fibronectin through Clustering of VLA-4 and VLA-5 Rosie Hart and David R. Greaves Chemerin is a potent macrophage chemoattractant protein. We used murine peritoneal exudate cells (PECs) in adhesion, flow cytom- etry, and confocal microscopy assays totestthehypothesisthat chemerin canalso contributetoinflammationby promoting macrophage adhesion. Chemerin stimulated the adhesion of PECs to the extracellular matrix protein fibronectin and to the adhesion molecule VCAM-1 within a minute, with an EC50 of 322 and 196 pM, respectively. Experiments using pertussis toxin and PECs from ChemR232/2 mice demonstrated that chemerin stimulated the adhesion of macrophages via the Gi protein-coupled receptor ChemR23. Blocking Abs against integrin subunits revealed that 89% of chemerin-stimulated adhesion to fibronectin was dependent on increased avidity of the integrin VLA-5 (a5b1) and that 88% of adhesion to VCAM-1 was dependent on increased avidity of VLA- Downloaded from 4(a4b1). Although chemerin was unable to induce an increase in integrin affinity as judged by the binding of soluble ligand, experiments using confocal microscopy revealed an increase in valency resulting from integrin clustering as the mechanism re- sponsible for chemerin-stimulated macrophage adhesion. PI3K, Akt, and p38 were identified as key signaling mediators in chemerin- stimulated adhesion. The finding that chemerin can rapidly stimulate macrophage adhesion to extracellular matrix proteins and adhesion molecules, taken together with its ability to promote chemotaxis, suggests a novel role for chemerin in the recruitment and retention of macrophages at sites of inflammation. The Journal of Immunology, 2010, 185: 3728–3739. http://www.jimmunol.org/ he coordinated recruitment of leukocytes to sites of tissue In addition to mediating chemotaxis, many chemoattractants, injury is central to the generation of a successful in- including chemokines, are also able to induce the adhesion of T flammatory response (1). The directed migration of leu- leukocytes to adhesion molecules, such as VCAM-1 and ICAM-1, kocytes is regulated by a number of inflammatory molecules in- and to extracellular matrix proteins, such as fibronectin, laminin, cluding chemokines, cytokines and complement proteins (2). and collagen IV (15). They induce adhesion by stimulating an Chemerin was originally isolated from human inflammatory exu- increase in the affinity and/or the valency of integrin receptors dates as the protein ligand for the orphan Gi-linked G protein- expressed on the cell surface (16). Leukocyte adhesion plays a key coupled receptor (GPCR) ChemR23 (3). ChemR23 is structurally role in inflammation, contributing to leukocyte rolling and arrest by guest on October 1, 2021 related to chemokine receptors, and accordingly, chemerin was dis- on the vascular endothelium, migration through the extracellular covered to possess the chemoattractant abilities of a chemokine (3, matrix to the site of inflammation, retention of leukocytes within 4). Chemerin is chemotactic for ChemR23-expressing human mac- the inflammatory site, and leukocyte activation (17–22). rophages, plasmacytoid dendritic cells (pDCs), and NK cells (3, 5– In this study, we hypothesized that chemerin may contribute to 7). ChemR23 is also expressed on human monocytes (6). In the mo- inflammation not only by mediating macrophage chemotaxis, but use, macrophages express ChemR23 and migrate toward chemerin also by promoting the adhesion of macrophages to extracellular (8, 9). Recently, murine pDCs and NK cells were also shown to be matrix proteins and adhesion molecules. ChemR23+ (10). Unlike the majority of chemokines, chemerin is secreted in an inactive precursor form (3). It requires cleavage of the Materials and Methods C terminus by serine proteases of the coagulation, fibrinolytic, and Animals inflammatory cascades to become active as a chemoattractant for All animal experiments were performed with ethical approval from the Dunn cells expressing ChemR23 (11–13). Moreover, chemerin’s predicted School of Pathology Local Ethical Review Committee and in accordance structure, thought to be the reverse orientation of that of chemokines, with the U.K. Home Office regulations (Guidance on the Operation of distinguishes it from this family of proteins (14). Animals, Scientific Procedures Act, 1986). Reagents Sir William Dunn School of Pathology, University of Oxford, Oxford, United King- Collagen IV, laminin and fibronectin were obtained Scientific Laboratory dom Supplies (Nottingham, U.K.). ICAM-1, VCAM-1, and VCAM-1-Fc were Received for publication July 6, 2009. Accepted for publication July 9, 2010. from R&D Systems (Abingdon, U.K.). The FITC-conjugated GRGDSP peptide was purchased from AnaSpec (Fremont, CA), as were all the blocking This work was supported by British Heart Foundation Grant FS/06/080. Abs and their isotype controls as follows: rat IgG1 (clone RTK2071), rat Address correspondence and reprint requests to Dr. David R. Greaves, Sir William IgG2a (clone RTK2758), rat IgG2b (clone RTK4530), Armenian hamster IgG Dunn School of Pathology, University of Oxford, South Parks Road, Oxford, Oxon (clone HTK888), anti-mouse CD18 (b2; clone M18/2), anti-mouse/rat OX1 3RE, U.K. E-mail address: [email protected] CD29 (b1; clone HMb1-1), anti-mouse CD49d (a4; clone R1-2), anti-mouse The online version of this article contains supplemental material. CD49e (a5; clone 5H10-27), anti-mouse CD51 (av; clone RMV-7), and anti- Abbreviations used in this paper: GPCR, G protein-coupled receptor; i.c., isotype mouse integrin b7 (clone FIB27). Of the inhibitors, Akt inhibitor IV, cyto- controls; LPAM, lymphocyte Peyer’s patch adhesion molecule; pDC, plasmacytoid chalasin D, LY294002, and SB202190 were purchased from Sigma-Aldrich dendritic cell; PEC, peritoneal exudate cell; PTX, pertussis toxin; WT, wild-type. (Gillingham, U.K.), BAPTA-AM and pertussis toxin (PTX) were from Cal- biochem (Nottingham, U.K.), piceatannol and PP2 were from Tocris Bio- Copyright Ó 2010 by The American Association of Immunologists, Inc. 0022-1767/10/$16.00 science (Bristol, U.K.), and U0126 was obtained from New England Biolabs www.jimmunol.org/cgi/doi/10.4049/jimmunol.0902154 The Journal of Immunology 3729 (Hitchin, U.K.). Anti-mouse CD16/CD32 (clone FCR4G8), FITC-conjugated Alexa Fluor 647-conjugated anti-mouse F4/80 and either 3 mg/ml PE- anti-mouse neutrophils (clone 7/4), Alexa Fluor 647-conjugated anti-mouse conjugated anti-mouse ChemR23 or 3 mg/ml PE-conjugated rat IgG2a F4/80 (clone CI:A3-1), FITC-conjugated anti-mouse CD49d (clone MFR5), isotype control for 30 min on ice, washed with assay buffer, and fixed with Pacific blue-conjugated anti-mouse F4/80 (clone CI:A3-1), and Alexa Fluor 2% formaldehyde (Sigma-Aldrich) in PBS. Cells were analyzed on a Cyan 647-conjugated anti-mouse CD206 (clone MR5D3) were from Serotec ADP flow cytometer (Dako, Ely, U.K.). Overnight-treated PECs were also (Oxford, U.K.). PE-conjugated anti-mouse ChemR23 (clone BZ194), PE- stained with 3 mg/ml FITC-conjugated anti-mouse CD80 or 1 mg/ml Alexa conjugated rat IgG2a isotype control (clone eBR2a), FITC-conjugated anti- Fluor 647-conjugated anti-mouse CD206 in combination with 2 mg/ml mouse CD49d (clone R1-2), FITC-conjugated rat IgG2a (clone eBR2a) and Pacific blue-conjugated anti-mouse F4/80. IgG2b (clone eB149/10H5), and FITC-conjugated anti-mouse CD80 (clone To measure the binding of a fibronectin peptide to macrophages, PECs 16-10A1) were purchased from eBioscience (Hatfield, U.K.). IFN-g and IL-4 from C57BL/6J mice were resuspended in assay buffer (HBSS [Invit- were from PeproTech (London, U.K.), and LPS was from Sigma-Aldrich. rogen] with CaCl2 and MgCl2 supplemented with 0.1% BSA and 20 mM Murine recombinant chemerin was obtained from R&D Systems, C15 was HEPES) to a concentration of 5 3 106 cells/ml, blocked with 10 mg/ml synthesized by Biosynthesis (Lewisville, TX), and C9 was a gift from anti-mouse CD16/CD32 for 15 min on ice, and stained with 1 mg/ml Alexa H. Wang and T. Schall (ChemoCentryx, Mountain View, CA). Fluor 647-conjugated anti-mouse F4/80 for 30 min on ice. FITC-labeled GRGDSP peptide (10 mM) and either assay buffer 10 mM MnCl2 (Sigma- Cells Aldrich) or 10 nM chemerin were added to 100 ml of the stained PECs and To obtain peritoneal exudate cells (PECs), Bio-Gel P100 polyacrylamide incubated at 37˚C for up to 5 min.
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