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Human Monocytes and Neutrophils Enhances the Proinflammatory Ligation of the FcRγ Chain-Associated Human Osteoclast-Associated Receptor Enhances the Proinflammatory Responses of Human Monocytes and Neutrophils This information is current as of September 24, 2021. Estelle Merck, Claude Gaillard, Mathieu Scuiller, Patrizia Scapini, Marco A. Cassatella, Giorgio Trinchieri and Elizabeth E. M. Bates J Immunol 2006; 176:3149-3156; ; doi: 10.4049/jimmunol.176.5.3149 Downloaded from http://www.jimmunol.org/content/176/5/3149 References This article cites 39 articles, 23 of which you can access for free at: http://www.jimmunol.org/ http://www.jimmunol.org/content/176/5/3149.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on September 24, 2021 • 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 © 2006 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Ligation of the FcR␥ Chain-Associated Human Osteoclast-Associated Receptor Enhances the Proinflammatory Responses of Human Monocytes and Neutrophils1 Estelle Merck,2* Claude Gaillard,* Mathieu Scuiller,* Patrizia Scapini,† Marco A. Cassatella,† Giorgio Trinchieri,3* and Elizabeth E. M. Bates4* We have previously described the human osteoclast associated receptor (hOSCAR), expressed in all cells of the myeloid lineage, and its immune functions. This receptor, which associates with the FcR␥ chain to transduce an activating signal, induces calcium flux in monocytes and dendritic cells, and modulates specific responses of dendritic cells. In this study, we have examined the effects of hOSCAR ligation on various proinflammatory responses of monocytes and neutrophils. Monocytes stimulated via hOSCAR ligation released IL-8/CXCL8 and other chemokines such as epithelial neutrophil-activating peptide-78/CXCL5, macrophage- Downloaded from derived chemokine/CCL22, and MCP-1/CCL2 and up-regulated markers involved in cell adhesion and costimulatory functions. Monocytes stimulated via hOSCAR in the absence of survival factors had an increased life span. Although the life span of neutrophils was unaffected, these cells, when stimulated via hOSCAR, rapidly released reactive oxygen intermediates, degranu- lated lactoferrin, myeloperoxidase, and matrix metalloproteinase-9 and also secreted IL-8/CXCL8. Neutrophils also underwent changes in cell surface molecule expression with the cleavage of CD62L and increased expression of CD11b and CD66b after 2-h stimulations. Finally, we demonstrated synergy between hOSCAR and TLR ligands on both monocytes and neutrophils, with up to 8-fold http://www.jimmunol.org/ increases in cytokine secretion when hOSCAR was cross-linked in the presence of LPS or R-848. Overall, our data demonstrate that hOSCAR is a functional receptor on monocytes and neutrophils, involved in the induction of the primary proinflammatory cascade and the initiation of downstream immune responses. The Journal of Immunology, 2006, 176: 3149–3156. onocytes, monocyte-derived macrophages, and neu- The ability of monocytes and neutrophils to respond to envi- trophils are phagocytic cells, the activation of which ronmental signals depends on the repertoire of plasma membrane M greatly contributes to the triggering and development receptors that they express and that allows them to recognize all of proinflammatory responses and the containment of infections. classes of macromolecules (4, 5). In this regard, a large number of These cells rapidly migrate through the endothelial barrier into receptors of the innate immune system use the ITAM signaling by guest on September 24, 2021 inflamed tissues, where they act as a first line of defense. Accord- pathway, which induces cellular activation via a phosphorylation ingly, monocytes and neutrophils, upon appropriate stimulation, cascade triggered by protein tyrosine kinases (6). ITAMs are release a number of proinflammatory mediators, including reactive mainly found in the cytoplasmic tail of transmembrane adaptors, oxygen intermediates and antimicrobial products, produce cyto- such as CD3␨, FcR␥, or DAP12, molecules that provide the role of kines and chemokines, modify the expression of surface mole- signaling subunits when associated with cell surface receptors. For cules, and efficiently phagocytose and kill invading pathogens (1, instance, the triggering receptor expressed on myeloid cells 2). The secretion of cytokines and chemokines by phagocytes at (TREM)5 family has recently attracted particular attention due to the infection site not only favors the recruitment of other effector the capacity of these DAP12-associated members to activate sev- cells (3), but also prepares and amplifies the subsequent immune eral myeloid cell types (7–9). Of interest, TREM-1 plays a crucial response. role in innate immunity, particularly during septic shock (10). In addition, TREM-1 engagement is able to enhance the responses of monocytes and neutrophils upon stimulation with TLR ligands (7, 11, 12). *Laboratory for Immunological Research, Schering-Plough Research Institute, Dar- Among the ITAM-linked receptors, the osteoclast-associated re- dilly, France; and †Department of Pathology, Division of General Pathology, Uni- versity of Verona, Verona, Italy ceptor (OSCAR), a myeloid cell receptor associated with the ␥ Received for publication August 19, 2005. Accepted for publication December ITAM-bearing chain FcR (13–15), has an expression pattern that 12, 2005. overlaps that of the TREM family. We have recently demonstrated The costs of publication of this article were defrayed in part by the payment of page that human OSCAR (hOSCAR) is expressed by myeloid dendritic charges. This article must therefore be hereby marked advertisement in accordance cells (DC), is involved in Ag internalization and presentation, and with 18 U.S.C. Section 1734 solely to indicate this fact. causes cellular activation and partial maturation in this cell type 1 E.M. was a recipient of a grant from the Fondation Marcel Me´rieux (Lyon, France). M.A.C. was supported by grants from Ministero dell’Istruzione, dell’Universita`e della Ricerca (Programmi di Ricerca di Interesse Nazionale 2003 and Fondo per gli Investimenti delle Ricerca di Base), from Associazione Italiana per la Ricerca sul 4 Current address: Molecular and Biochemical Analytical Services, Bayer BioScience Cancro, and Fondazione Cassa di Risparmio di Verona-Vicenza-Ancona e Belluno. N.V., Technologiepark 38, 9052 Gent, Belgium. 2 Address correspondence and reprint requests to Dr. Estelle Merck at the current 5 Abbreviations used in this paper: TREM, triggering receptor expressed on myeloid address: Ludwig Institute for Cancer Research, Chemin des Boveresses 155, 1066 cells; OSCAR, osteoclast-associated receptor; hOSCAR, human OSCAR; DC, den- Epalinges, Switzerland. E-mail address: [email protected] dritic cell; GAM, goat anti-mouse; MMP-9, matrix metalloproteinase-9; MPO, my- 3 Current address: Laboratory of Parasitic Disease, National Institute of Allergy and eloperoxidase; ROI, reactive oxygen intermediate; MDC, macrophage-derived Infectious Diseases, National Institutes of Health, Bethesda, MD. chemokine. Copyright © 2006 by The American Association of Immunologists, Inc. 0022-1767/06/$02.00 3150 ACTIVATION VIA hOSCAR ENHANCES PROINFLAMMATORY RESPONSES (14, 16). In addition, we have shown that numerous DC functions maintain cellular integrity in culture. After the indicated incubation times, triggered by hOSCAR stimulation are negatively regulated by the cells were harvested and apoptotic cells were detected using the FITC- ITIM-signaling receptor CD85j (leukocyte Ig-like receptor-1/Ig- Annexin V kit (BD Pharmingen) followed by flow cytometer analysis. like transcript 2), confirming that hOSCAR is a classical ITAM- Measurement of soluble mediator release linked receptor that plays a role in maintaining the equilibrium of Supernatants of cells stimulated for the times indicated in the results were the immune response (17). Some of those studies (14, 16) also collected and tested by ELISA for production of IL-1␤, IL-6, IL-8/CXCL8, described the role of hOSCAR in adaptive immunity and under- IL-10, IL-12 p40, TNF, MCP-1/CCL2, GM-CSF (OptEIA kits; BD Pharm- lined differences between FcR␥- and DAP12-associated receptors. ingen), epithelial neutrophil-activating peptide-78/CXCL5, macrophage- Despite the increasing understanding of the role of hOSCAR in derived chemokine (MDC)/CCL22, M-CSF, matrix metalloproteinase-9 (MMP-9) (DuoSet kit; R&D Systems), and myeloperoxidase (MPO) DC biology, no information has been reported on the potential role (Merck Calbiochem). The detection of lactoferrin was performed as pre- of hOSCAR in modulating the effector functions of phagocytic viously described (20). Briefly, supernatants were diluted in 0.05 M car- cells. bonate buffer (pH 9.6) and proteins were immobilized in Nunc-Immuno In the present work, we have investigated the capacity
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