Mycobacterial lipomannan induces granuloma macrophage fusion via a TLR2-dependent, ADAM9- and beta1 integrin-mediated pathway.
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.
Puissegur
Marie-Pierre
MP
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.
Lay
Guillaume
G
Gilleron
Martine
M
Botella
Laure
L
Nigou
Jérôme
J
Marrakchi
Hedia
H
Mari
Bernard
B
Duteyrat
Jean-Luc
JL
Guerardel
Yann
Y
Kremer
Laurent
L
Barbry
Pascal
P
Puzo
Germain
G
Altare
Frédéric
F
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*
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