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Mycobacterial Lipomannan Induces Granuloma Macrophage Fusion via a TLR2-Dependent, ADAM9- and ₁ Integrin-Mediated Pathway¹

Marie-Pierre Puissegur^2,*, Guillaume Lay^2,*, Martine Gilleron, Laure Botella^*, Jérôme Nigou, Hedia Marrakchi^*, Bernard Mari^,, Jean-Luc Duteyrat^¶, Yann Guerardel^||, Laurent Kremer^#, Pascal Barbry^,, Germain Puzo and Frédéric Altare^3,*

^* Laboratory of Molecular Physiology of Mycobacterial Granulomas and Laboratory of Immunochemistry of Mycobacterial Glycoconjugates, Department of Molecular Mechanisms of Mycobacterial Infections, Institut de Pharmacologie et de Biologie Structurale, Centre National de la Recherche Scientifique Unité Mixte de Recherche 5089, Toulouse, France; Centre National de la Recherche Scientifique and University of Nice Sophia Antipolis, Institut de Pharmacologie Moléculaire et Cellulaire, Unité Mixte de Recherche 6097, Sophia Antipolis, France; ^¶ Electron Microscopy Department, Rangueil Hospital Medical School, University of Toulouse, Toulouse, France; ^|| Unité de Glycobiologie Structurale et Fonctionnelle, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8576, Villeneuve d’Ascq, France; and ^# Laboratoire de Dynamique Moléculaire des Interactions Membranaires, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5539, Université des Sciences et Techniques du Languedoc, Montpellier II, Montpellier, France

Tuberculous granulomas are the sites of interaction between the host response and the tubercle bacilli within infected individuals. They mainly consist of organized aggregations of lymphocytes and macrophages (Mf). A predominant role of mycobacterial envelope glycolipids in granulomas formation has been recently emphasized, yet the signaling events interfering with granuloma cell differentiation remain elusive. To decipher this molecular machinery, we have recently developed an in vitro human model of mycobacterial granulomas. In this study, we provide evidence that the mycobacterial proinflammatory phosphatidyl-myo-inositol mannosides and lipomannans (LM), as well as the anti-inflammatory lipoarabinomannan induce granuloma formation, yet only the proinflammatory glycolipids induce the fusion of granuloma Mf into multinucleated giant cells (MGC). We also demonstrate that LM induces large MGC resembling those found in vivo within the granulomas of tuberculosis patients, and that this process is mediated by TLR2 and is dependent on the ₁ integrin/ADAM9 cell fusion machinery. Our results demonstrate for the first time that the Mf differentiation stage specifically occurring within granulomatous structures (i.e., MGC formation) is triggered by mycobacterial envelope glycolipids, which are capable of inducing the cell fusion machinery. This provides the first characterization of the ontogeny of human granuloma MGC, thus resulting in a direct modulation by a particular mycobacterial envelope glycolipid of the differentiation process of granuloma Mf.

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 FP6 TB-VAC Project (LSHP-CT2003-503367) and the Fondation pour la Recherche Médicale. M.P.P. and G.L. were supported by the Ministére de l’Education Nationale. L.K. was supported by a grant from the Centre National de la Recherche Scientifique Action Thématique et Incitative sur Programme Microbiologie Fondamentale.

² M.-P.P. and G.L. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Frédéric Altare, Laboratory of Molecular Physiology of Mycobacterial Granuloma, Department of Molecular Mechanisms of Mycobacterial Infections, Institut de Pharmacologie et Biologie Structurale-Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5089, 205 Route de Narbonne, Toulouse, France. E-mail address: frederic.altare{at}ipbs.fr

⁴ Abbreviations used in this paper: TB, tuberculosis; Mf, macrophage; Ly, lymphocyte; MGC, multinucleated giant cell; TDM, trehalose-6,6'-dimycolate; PIM, phosphatidyl-myo-inositol mannoside; LM, lipomannan; LAM, lipoarabinomannan; ManLAM, mannose-capped LAM; PI, phosphatidyl inositol; ITG1, ₁ integrin; MGG, May-Grünwald-Giemsa; s.e.m., scanning electron microscopy; aRNA, antisense RNA; n.s., nonstimulated.

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