title: Mycobacterial lipomannan induces granuloma macrophage fusion via a TLR2-dependent, ADAM9- and beta1 integrin-mediated pathway.
abstract: 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 beta(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.
authors.affiliation: Laboratory of Molecular Physiology of Mycobacterial Granulomas, Department of Molecular Mechanisms of Mycobacterial Infections, Institut de Pharmacologie et Biologie Structurale, CNRS/UMR 5089, 205 Route de Narbonne, Toulouse, France.
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Puissegur
authors.forename: Guillaume
authors.initials: G
authors.lastname: Lay
authors.forename: Martine
authors.initials: M
authors.lastname: Gilleron
authors.forename: Laure
authors.initials: L
authors.lastname: Botella
authors.forename: Jérôme
authors.initials: J
authors.lastname: Nigou
authors.forename: Hedia
authors.initials: H
authors.lastname: Marrakchi
authors.forename: Bernard
authors.initials: B
authors.lastname: Mari
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Duteyrat
authors.forename: Yann
authors.initials: Y
authors.lastname: Guerardel
authors.forename: Laurent
authors.initials: L
authors.lastname: Kremer
authors.forename: Pascal
authors.initials: P
authors.lastname: Barbry
authors.forename: Germain
authors.initials: G
authors.lastname: Puzo
authors.forename: Frédéric
authors.initials: F
authors.lastname: Altare
mesh_terms: D051722:ADAM Proteins / Q000276:immunology*; D016667:Bacterial Capsules / Q000737:chemistry / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects; D002459:Cell Fusion; D002478:Cells, Cultured; D015726:Giant Cells / Q000648:ultrastructure; D006099:Granuloma / Q000139:chemically induced / Q000276:immunology*; D006801:Humans; D019012:Integrin beta1 / Q000276:immunology*; D008070:Lipopolysaccharides / Q000737:chemistry / Q000276:immunology* / Q000494:pharmacology; D008264:Macrophages / Q000276:immunology* / Q000648:ultrastructure; D008565:Membrane Proteins / Q000276:immunology*; D009161:Mycobacterium / Q000737:chemistry / Q000276:immunology*; D051195:Toll-Like Receptor 2 / Q000276:immunology*
chemical_list: D019012:Integrin beta1; D008070:Lipopolysaccharides; D008565:Membrane Proteins; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2; C064351:lipomannan; D051722:ADAM Proteins; C098339:ADAM9 protein, human