title: Acylation determines the toll-like receptor (TLR)-dependent positive versus TLR2-, mannose receptor-, and SIGNR1-independent negative regulation of pro-inflammatory cytokines by mycobacterial lipomannan.
abstract: Mycobacterium tuberculosis lipomannans (LMs) modulate the host innate immune response. The total fraction of Mycobacterium bovis BCG LM was shown both to induce macrophage activation and pro-inflammatory cytokines through Toll-like receptor 2 (TLR2) and to inhibit pro-inflammatory cytokine production by lipopolysaccharide (LPS)-activated macrophages through a TLR2-independent pathway. The pro-inflammatory activity was attributed to tri- and tetra-acylated forms of BCG LM but not the mono- and di-acylated ones. Here, we further characterize the negative activities of M. bovis BCG LM on primary murine macrophage activation. We show that di-acylated LMs exhibit a potent inhibitory effect on cytokine and NO secretion by LPS-activated macrophages. The inhibitory activity of mycobacterial mannose-capped lipoarabino-mannans on human phagocytes was previously attributed to their binding to the C-type lectins mannose receptor or specific intracellular adhesion molecule-3 grabbing nonintegrin (DC-SIGN). However, we found that di-acylated LM inhibition of LPS-induced tumor necrosis factor secretion by murine macrophages was independent of TLR2, mannose receptor, or the murine ortholog SIGNR1. We further determined that tri-acyl-LM, an agonist of TLR2/TLR1, promoted interleukin-12 p40 and NO secretion through the adaptor proteins MyD88 and TIRAP, whereas the fraction containing tetra-acylated LM activated macrophages in a MyD88-dependent fashion, mostly through TLR4. TLR4-dependent pro-inflammatory activity was also seen with M. tuberculosis LM, composed mostly of tri-acylated LM, suggesting that acylation degree per se might not be sufficient to determine TLR2 versus TLR4 usage. Therefore, LM acylation pattern determines the anti-inflammatory versus pro-inflammatory effects of LM through different pattern recognition receptors or signaling pathways and may represent an additional mean of regulating the host innate immunity by mycobacteria.
authors.affiliation: Orleans University and CNRS, Molecular Immunology and Embryology, UMR6218, 45071 Orléans, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Doz
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Rose
authors.forename: Jérôme
authors.initials: J
authors.lastname: Nigou
authors.forename: Martine
authors.initials: M
authors.lastname: Gilleron
authors.forename: Germain
authors.initials: G
authors.lastname: Puzo
authors.forename: François
authors.initials: F
authors.lastname: Erard
authors.forename: Bernhard
authors.initials: B
authors.lastname: Ryffel
authors.forename: Valerie F J
authors.initials: VF
authors.lastname: Quesniaux
mesh_terms: D000215:Acylation; D000818:Animals; D015815:Cell Adhesion Molecules / Q000276:immunology* / Q000378:metabolism; D002460:Cell Line; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D053762:Interleukin-12 Subunit p40 / Q000276:immunology*; D037181:Lectins, C-Type / Q000276:immunology* / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology; D008262:Macrophage Activation / Q000187:drug effects / Q000276:immunology; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000276:immunology* / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009163:Mycobacterium bovis / Q000276:immunology*; D009169:Mycobacterium tuberculosis / Q000276:immunology; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology / Q000378:metabolism; D009569:Nitric Oxide / Q000276:immunology / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000276:immunology* / Q000378:metabolism; D017472:Receptors, Interleukin-1 / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D051194:Toll-Like Receptor 1 / Q000819:agonists / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000819:agonists / Q000276:immunology* / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000819:agonists / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology* / Q000378:metabolism; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
chemical_list: D015815:Cell Adhesion Molecules; D053762:Interleukin-12 Subunit p40; D037181:Lectins, C-Type; D008070:Lipopolysaccharides; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D008562:Membrane Glycoproteins; D053594:Myeloid Differentiation Factor 88; D009569:Nitric Oxide; D011956:Receptors, Cell Surface; D017472:Receptors, Interleukin-1; D051194:Toll-Like Receptor 1; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin; C500879:IL12B protein, human; C507779:MYD88 protein, human; C507780:Myd88 protein, mouse; C434984:TIRAP protein, human; C499045:TIRAP protein, mouse; C495342:TLR2 protein, human; C495345:TLR4 protein, human; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; C050016:lipoarabinomannan; C064351:lipomannan