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Involvement of the Purinergic P2X₇ Receptor in the Formation of Multinucleated Giant Cells¹

Irma Lemaire^2,*, Simonetta Falzoni, Natacha Leduc^*, Bin Zhang^*, Patrizia Pellegatti, Elena Adinolfi, Paola Chiozzi and Francesco Di Virgilio

^* Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada; and Department of Experimental and Diagnostic Medicine, Section of General Pathology and Interdisciplinary Center for the Study of Inflammation, University of Ferrara, Ferrara, Italy

Multinucleated giant cells (MGC), a hallmark of chronic inflammatory reactions, remain an enigma of cell biology. There is evidence implicating the purinergic P2X₇ receptor in the fusion process leading to MGC. To investigate this, we used HEK 293 cells stably transfected with either 1) the full-length rat P2X₇ receptor (P2X₇ cells), 2) a rat P2X₇ receptor lacking the C-terminal domain (P2X₇TC), or 3) a mock vector, and rat alveolar macrophages (MA) expressing the native receptor. P2X₇ cells cultured in serum-free medium formed increased numbers of MGC and displayed a higher fusion index compared with mock transfectants. Stimulation of P2X₇ pore-forming activity in P2X₇ cells by polymyxin B (PMB) further increased significantly the formation of MGC. Conversely, blockers of P2X-receptors including oxidized ATP, brilliant blue G, and pyridoxal phosphate-6-azophenyl-2'-4'-disulfonic acid inhibited significantly MGC formation in both unstimulated and PMB-stimulated P2X₇-transfected cells. In contrast, cells transfected with the truncated P2X₇TC were devoid of pore-forming activity, did not respond to PMB stimulation, and failed to form enhanced numbers of MGC, thus behaving as mock transfectants. As found for P2X₇-transfected cells, PMB also potentiated dose-dependently the formation of multinucleated MA by rat alveolar MA. Pretreatment with oxidized ATP abrogated the PMB stimulatory effects. Together, these data demonstrate unequivocally the participation of P2X₇ receptor in the process of MGC formation. Our study also provides evidence suggesting that stimulation of the P2X₇ receptor pathway in MA may mediate increased formation of MGC during chronic inflammatory reactions.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from the Natural Sciences and Engineering Research Council of Canada, the Canadian Institutes of Health Research, the Italian Association for Cancer Research, the Italian Ministry of Education and Scientific Research, the National Research Council of Italy and the Italian Space Agency. I.L. was recipient of a Canadian Institutes of Health Research-National Research Council (Italy) International Scientific Exchange Award.

² Address correspondence and reprint requests to Dr. Irma Lemaire, Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada K1H 8M5. E-mail address: ilemaire{at}uottawa.ca

³ Abbreviations used in this paper: MA, macrophage; MGC, multinucleated giant cell; FBGC, foreign body giant cell; oATP, oxidized ATP; PMB, polymyxin B; BBG, brilliant blue G; PPADS, pyridoxal phosphate-6-azophenyl-2'-4'-disulfonic acid; EtBr, ethidium bromide; BAL, bronchoalveolar lavage; f.i., fusion index.

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