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ICOS-Ligand Triggering Impairs Osteoclast Differentiation and Function in Vitro and in Vivo

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ICOS-Ligand Triggering Impairs Osteoclast Differentiation and Function in Vitro and in Vivo ICOS-Ligand Triggering Impairs Osteoclast Differentiation and Function In Vitro and In Vivo This information is current as Casimiro L. Gigliotti, Elena Boggio, Nausicaa Clemente, of November 9, 2016. Yogesh Shivakumar, Erika Toth, Daniele Sblattero, Patrizia D'Amelio, Giovanni C. Isaia, Chiara Dianzani, Junji Yagi, Josè M. Rojo, Annalisa Chiocchetti, Renzo Boldorini, Michela Bosetti and Umberto Dianzani J Immunol 2016; 197:3905-3916; Prepublished online 19 Downloaded from October 2016; doi: 10.4049/jimmunol.1600424 http://www.jimmunol.org/content/197/10/3905 http://www.jimmunol.org/ Supplementary http://www.jimmunol.org/content/suppl/2016/10/19/jimmunol.160042 Material 4.DCSupplemental.html References This article cites 49 articles, 14 of which you can access for free at: http://www.jimmunol.org/content/197/10/3905.full#ref-list-1 Subscriptions Information about subscribing to The Journal of Immunology is online at: at Bibl Unito on November 9, 2016 http://jimmunol.org/subscriptions Permissions Submit copyright permission requests at: http://www.aai.org/ji/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/cgi/alerts/etoc The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 9650 Rockville Pike, Bethesda, MD 20814-3994. Copyright © 2016 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology ICOS-Ligand Triggering Impairs Osteoclast Differentiation and Function In Vitro and In Vivo Casimiro L. Gigliotti,*,1 Elena Boggio,*,1 Nausicaa Clemente,* Yogesh Shivakumar,* Erika Toth,* Daniele Sblattero,* Patrizia D’Amelio,† Giovanni C. Isaia,† Chiara Dianzani,‡ Junji Yagi,x Jose` M. Rojo,{ Annalisa Chiocchetti,* Renzo Boldorini,* Michela Bosetti,‖ and Umberto Dianzani* Osteoblasts, osteocytes, and osteoclasts (OCs) are involved in the bone production and resorption, which are crucial in bone ho- meostasis. OC hyperactivation plays a role in the exaggerated bone resorption of diseases such as osteoporosis, rheumatoid arthritis, and osteolytic tumor metastases. This work stems from the finding that OCs can express B7h (ICOS-Ligand), which is the ligand of the ICOS T cell costimulatory molecule. Because recent reports have shown that, in endothelial, dendritic, and tumor cells, B7h Downloaded from triggering modulates several activities of these cells, we analyzed the effect of B7h triggering by recombinant ICOS-Fc on OC differentiation and function. The results showed that ICOS-Fc inhibits RANKL-mediated differentiation of human monocyte- derived OC-like cells (MDOCs) by inhibiting the acquirement of the OC morphology, the CD142 cathepsin K+ phenotype, and the expression of tartrate-resistant acid phosphatase, OSCAR, NFATc1, and DC-STAMP. Moreover, ICOS-Fc induces a reversible decrease in the sizes of cells and nuclei and cathepsin K expression in mature MDOCs. Finally, ICOS-Fc inhibits the osteolytic activities of MDOCs in vitro and the development of bone loss in ovariectomized or soluble RANKL-treated mice. These findings http://www.jimmunol.org/ open a novel field in the pharmacological use of agonists and antagonists of the ICOS–B7h system. The Journal of Immunology, 2016, 197: 3905–3916. he inducible costimulator ligand or B7h (CD275, also activated T cells, whereas B7h is expressed by a wide variety of known as ICOSL, B7H2, B7-RP1, GL50) belongs to the cell types, including B cells, macrophages, and dendritic cells T B7 family of surface receptors and binds ICOS (CD278), (DCs). However, B7h is also expressed by cells of nonhemopoietic which belongs to the CD28 family (1–5). ICOS is expressed by origin such as vascular endothelial cells (ECs), epithelial cells, and fibroblasts, and many tumor cells. The main known function at Bibl Unito on November 9, 2016 of B7h is the triggering of ICOS, which acts as a costimulatory *Department of Health Sciences and Interdisciplinary Research Center of Autoimmune molecule for activated T cells by modulating their cytokine se- † Diseases, University of Piemonte Orientale, 28100 Novara, Italy; Department of cretion and, particularly, increasing the secretion of IFN-g (in Medical Sciences, University of Torino, 10126 Torino, Italy; ‡Department of Drug Science and Technology, University of Torino, 10125 Torino, Italy; xDepartment of humans), IL-4 (in mice), IL-10, IL-17, and IL-21 (in both species) Microbiology and Immunology, Tokyo Women’s Medical University, Tokyo 108-8639, { (6–11). However, recent reports have shown that the B7h–ICOS Japan; Departamento de Medicina Celular y Molecular, Centro de Investigaciones interaction can trigger bidirectional signals able to modulate also Biologicas, Consejo Superior de Investigaciones Cientificas, 28006 Madrid, Spain; and ‖Department of Pharmaceutical Sciences, University of Piemonte Orientale, 28100 the response of the B7h-expressing cells. In mouse DCs, this B7h- Novara, Italy mediated reverse signaling induces partial maturation with 1C.L.G. and E.B. contributed equally to this work. prominent augmentation of IL-6 secretion (12). In human DCs, it ORCIDs: 0000-0002-3127-5686 (C.L.G.); 0000-0003-2700-3597 (E.B.); 0000-0002- modulates cytokine secretion, promotes the capacity to cross-present 9860-0148 (N.C.); 0000-0003-2669-6328 (E.T.); 0000-0003-4309-242X (D.S.); endocytosed Ags in class I MHC molecules, and inhibits adhe- 0000-0001-9032-0072 (J.M.R.); 0000-0002-3682-8702 (M.B.). siveness to ECs and migration (13, 14). B7h stimulation also Received for publication March 14, 2016. Accepted for publication September 20, 2016. inhibits the adhesiveness and migration of ECs and tumor cell lines in vitro and development of experimental lung metastases This work was supported by the Associazione Italiana Ricerca sul Cancro (Grant IG 14430; Milan), the Fondazione Amici di Jean (Torino), and the Fondazione Cassa di in vivo (15, 16). These effects are accompanied by decreased Risparmio di Cuneo (Cuneo). phosphorylation of ERK and p38 in ECs, decreased phosphor- U.D., G.C.I., and C.D. designed research; C.L.G., E.B., N.C., and Y.S. performed ylation of focal adhesion kinase, and downmodulation of b-Pix research; E.T. and D.S. contributed reagents and tools; P.D., A.C., R.B., and M.B. in ECs and tumor cells. Moreover, triggering of B7h potentiates analyzed data; and U.D., J.Y., and J.M.R. wrote the article. signaling via several pattern recognition receptors in human DCs Address correspondence and reprint requests to Dr. Umberto Dianzani, Department of Health Sciences, Interdisciplinary Research Center of Autoimmune Diseases, through a signaling pathway involving the adaptor protein re- University of Piemonte Orientale, Via Solaroli 17, 28100 Novara, Italy. E-mail ceptor for activated C kinase 1 and the kinases protein kinase address: [email protected] C (PKC) and JNK (14). The online version of this article contains supplemental material. The aim of our research was to extend these analyses by in- Abbreviations used in this article: DC, dendritic cell; EC, endothelial cell; MA, vestigating the expression and function of B7h in osteoclasts (OCs), medullary area; MDOC, monocyte-derived OC-like cell; OB, osteoblast; OC, oste- oclast; OPG, osteoprotegerin; OVX, ovariectomy; PKC, protein kinase C; RA, rheu- which derive from the monocyte lineage, similarly to DCs. OCs are matoid arthritis; RANK, receptor activator of NF-kB; RANKL, RANK ligand; T, giant cells formed by the cell–cell fusion of monocyte-macrophage day; TA, total area of the bone; TRAP, tartrate-resistant acid phosphatase; Treg, precursors and are characterized by multiple nuclei, abundant regulatory T cell; TRITC, tetramethylrhodamine B isothiocyanate. vacuoles, and lysosomes; they play a key role in bone remodeling, Copyright Ó 2016 by The American Association of Immunologists, Inc. 0022-1767/16/$30.00 which also involves osteoblasts (OBs) and osteocytes. OCs differentiate www.jimmunol.org/cgi/doi/10.4049/jimmunol.1600424 3906 ICOSL FUNCTION IN OSTEOCLASTS from monocytes under the influence of M-CSF and the receptor human ICOS amino acid sequence. For analysis, MDOCs were detached activator of NF-kB (RANK) ligand (RANKL) (17–21). from the plates using the TrypLE express reagent (Life Technologies, The OC function is stimulated by the triggering of the RANK Carlsbad, CA) for 15 min before using a cell scraper (31). Cell viability detected by trypan blue exclusion assay was .98%. expressed on the membrane of OCs by RANKL. In healthy bone, RANKL is mainly expressed by OBs as a surface receptor in re- Immunofluorescence sponse to bone-resorbing factors, and it is cleaved into a soluble The OCs phenotype was assessed by immunofluorescence and flow molecule by metalloproteinases. Moreover, RANKL is also ex- cytometry (BD Biosciences, San Diego, CA) using the FITC-, PE-, and pressed by stromal cells, lymphocytes, and macrophages, which allophycocyanin-conjugated mAbs to CD14 (Immunotools, Friesoythe, can support OC function during inflammation. Osteoprotegerin Germany), cathepsin K (Bioss, Woburn, MA), and B7h (R&D Systems). Cathepsin K was evaluated after cell permeabilization using the FIX and (OPG) is a soluble decoy receptor of RANKL secreted by OBs and PERM kit (Invitrogen). stromal cells; OPG prevents RANK stimulation by inhibiting its Actin and B7h staining were performed on cells cultured on glass binding to RANKL and impairs osteoclastogenesis (22). The coverslips, fixed with 4%
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