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Antigen Receptor for Chemokines Migration Through the Decoy Receptor Duffy CXCL1 Inhibits Airway Smooth Muscle Cell

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Antigen Receptor for Chemokines Migration Through the Decoy Receptor Duffy CXCL1 Inhibits Airway Smooth Muscle Cell CXCL1 Inhibits Airway Smooth Muscle Cell Migration through the Decoy Receptor Duffy Antigen Receptor for Chemokines This information is current as Laila A. Al-Alwan, Ying Chang, Simon Rousseau, James G. of September 23, 2021. Martin, David H. Eidelman and Qutayba Hamid J Immunol 2014; 193:1416-1426; Prepublished online 30 June 2014; doi: 10.4049/jimmunol.1302860 http://www.jimmunol.org/content/193/3/1416 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2014/06/30/jimmunol.130286 Material 0.DCSupplemental http://www.jimmunol.org/ References This article cites 62 articles, 13 of which you can access for free at: http://www.jimmunol.org/content/193/3/1416.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on September 23, 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 © 2014 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology CXCL1 Inhibits Airway Smooth Muscle Cell Migration through the Decoy Receptor Duffy Antigen Receptor for Chemokines Laila A. Al-Alwan,1 Ying Chang,1 Simon Rousseau, James G. Martin, David H. Eidelman, and Qutayba Hamid Airway smooth muscle cell (ASMC) migration is an important mechanism postulated to play a role in airway remodeling in asthma. CXCL1 chemokine has been linked to tissue growth and metastasis. In this study, we present a detailed examination of the inhibitory effect of CXCL1 on human primary ASMC migration and the role of the decoy receptor, Duffy AgR for chemokines (DARC), in this inhibition. Western blots and pathway inhibitors showed that this phenomenon was mediated by activation of the ERK-1/2 MAPK pathway, but not p38 MAPK or PI3K, suggesting a biased selection in the signaling mechanism. Despite being known as a non- Downloaded from signaling receptor, small interference RNA knockdown of DARC showed that ERK-1/2 MAPK activation was significantly depen- dent on DARC functionality, which, in turn, was dependent on the presence of heat shock protein 90 subunit a. Interestingly, DARC- or heat shock protein 90 subunit a–deficient ASMCs responded to CXCL1 stimulation by enhancing p38 MAPK activation and ASMC migration through the CXCR2 receptor. In conclusion, we demonstrated DARC’s ability to facilitate CXCL1 inhibition of ASMC migration through modulation of the ERK-1/2 MAPK–signaling pathway. The Journal of Immunology, 2014, 193: 1416–1426. http://www.jimmunol.org/ tructural cell migration is a central mechanism involved in viability, would disrupt the active recruitment of cells, potentially a range of physiological conditions, such as wound healing providing an avenue for therapeutic intervention. S (1), neurogenesis (2), and embryogenesis (3). This very Recently, we demonstrated that IL-17–induced CXC chemo- fundamental mechanism may have detrimental consequences for kines, also known as growth-related oncogenes (GROs), CXCL1 tissue structure and function when migration leads to an exces- (GRO-a), CXCL2 (GRO-b), and CXCL3 (GRO-g), had the po- sive accumulation of cells. Tissue fibrosis (4), inappropriate angio- tential to collectively induce ASMC migration (15). Although genesis (5), cancer cell metastasis (6), and increased airway smooth primarily known as a potent inducer of neutrophil chemotaxis by guest on September 23, 2021 muscle mass in asthma (7) are a few examples of progressively (16), CXCL1 was shown to induce cancer cell invasion (17) and disproportionate cell migration. Attempts have been made to endothelial (18) and epithelial cell migration (19). CXCL1 facil- understand the source of migrating cells (8–12) with the hope of itates its signaling by binding to its putative receptor, the che- better understanding the role of migration in diseases such as mokine receptor CXCR2, although it also was found to bind to asthma, where the origins of migrating cells are not known in vivo CXCR1, albeit with lower affinity (20). Chemokine receptors (13) and, hence, cannot be specifically targeted. However, regard- belong to class A rhodopsin-like, seven-transmembrane, or hep- less of the origins of migrating cells, active recruitment of cells tahelical, G protein–coupled receptors (GPCRs), which in general, from different sites, near or far, is central for disease chronicity and favor coupling to the Gai protein subunit (21). severity (8, 14). Therefore, it is possible to speculate that interfer- Consisting of more than 1000 receptors capable of mediating ence with the machinery of cell migration, without affecting cellular multiple biological functions, GPCRs are amenable targets for drug development (22). The classical view of GPCR signaling requires their association with a heterotrimeric complex of small G pro- Meakins-Christie Laboratories, Respiratory Division, Department of Medicine, McGill University, Montreal, Quebec H2X 2P2, Canada teins (Gabg) through a highly conserved DRYLAIV motif in 1L.A.A.-A. and Y.C. contributed equally to this work. the second loop near the C terminus of the GPCR (23). Atypical Received for publication October 23, 2013. Accepted for publication May 26, 2014. or decoy receptors are a group of seven-transmembrane receptors This work was supported by the Canadian Institutes of Health Research, the Amer- that are unable to recruit small G proteins and, hence, cannot ican Thoracic Society, the Costello Memorial Fund, and the McGill University activate classical GPCR signaling. There are four known atypical Health Centre-Research Institute of the Fonds de la Recherche en Sante´ Que´bec. receptors: D6, CCX-CKR1, CXCR7, and Duffy AgR for chemo- Address correspondence and reprint requests to Dr. Qutayba Hamid, Meakins-Christie kines (DARC) (23). The lack of signaling by these receptors is Laboratories, Respiratory Division, Department of Medicine, McGill University, 3626 Rue St. Urbain, Montreal, QC H2X 2P2, Canada. E-mail address: Qutayba.Hamid@ ascribed either to the complete absence of the DRYLAIV motif, as McGill.ca is the case for DARC, or to the presence of presumably non- The online version of this article contains supplemental material. functional modified forms of this motif (DKYLEIV in D6, DRY- Abbreviations used in this article: 17-AAG, 17-N-allylamino-17-demethoxygeldana- VAVT in CCX-CKR1, and DRYLSIT in CXCR7) (23). DARC mycin; ASMC, airway smooth muscle cell; DARC, Duffy AgR for chemokines; Gai- was first discovered on RBCs as the Duffy blood group Ag (24) PCR; Gai–protein-coupled receptor; GPCR, G protein–coupled receptor; GRO, growth-related oncogene; HSP, heat shock protein; PDGF, platelet-derived growth and was subsequently shown to serve as a receptor for the malarial factor; PI, propidium iodide; Ptx, pertussis toxin; rh, recombinant human; RT, room parasites Plasmodium vivax and Plasmodium knowlesi (25, 26). temperature; siRNA, small interference RNA; siScram, scrambled siRNA. DARC has been established as a promiscuous chemokine receptor Copyright Ó 2014 by The American Association of Immunologists, Inc. 0022-1767/14/$16.00 that can bind several chemokines, including CXCL1, to which it www.jimmunol.org/cgi/doi/10.4049/jimmunol.1302860 The Journal of Immunology 1417 binds with the highest affinity (27). The expression of KC (the Small interference RNA transfection mouse ortholog of human CXCL1) and DARC was found to ASMCs were grown to 60–80% confluence in medium containing 10% follow parallel temporal patterns and tissue localization during FBS. The cells were transfected with small interference RNA (siRNA) mouse development (28), suggesting that a relationship may exist targeting CXCR1 and/or CXCR2, DARC, or HSP90a using the siRNA between the two. In general, DARC was found to maintain che- Reagent System (all from Santa Cruz Biotechnology, Santa Cruz, CA). mokine homeostasis in the blood (29) and to facilitate chemokine Scrambled siRNAs (Santa Cruz Biotechnology) were used as a negative control. After transfection, ASMCs were either used directly for migration transcytosis and presentation across endothelium (30, 31). experiments or stimulated with CXCL1 and prepared for Western blotting. In this study, we investigated the effect of CXCL1 on ASMC Protein lysates from transfected, nonstimulated ASMCs were saved to migration and the role of CXCR1, CXCR2, and DARC in medi- evaluate the efficiency of siRNA knockdown by Western blotting using anti- ating this effect. Our results establish that CXCL1 inhibits ASMC CXCR2 (Abcam, Cambridge, MA), anti-CXCR1 (R&D Systems, Minne- apolis, MN), anti-DARC (Abcam), or anti-HSP90a (Abcam) Abs. GAPDH migration through activation of the ERK-1/2 MAPK pathway (Millipore, Billerica, MA) was used as a loading control. and that this effect is mediated via DARC but not the CXCR1 or CXCR2 receptors. In addition, we observed a regulatory effect of Immunofluorescence staining the heat shock protein (HSP)90a on DARC protein expression in ASMCs were seeded
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