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.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Acylation
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Animals
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Cell Adhesion Molecules / immunology*
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Cell Adhesion Molecules / metabolism
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Cell Line
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Humans
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Immunity, Innate* / drug effects
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Inflammation / immunology
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Inflammation / metabolism
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Interleukin-12 Subunit p40 / immunology*
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Lectins, C-Type / immunology*
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Lectins, C-Type / metabolism
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Lipopolysaccharides / immunology*
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Lipopolysaccharides / metabolism
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Lipopolysaccharides / pharmacology
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Macrophage Activation / drug effects
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Macrophage Activation / immunology
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Macrophages / immunology*
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Macrophages / metabolism
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Mannose Receptor
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Mannose-Binding Lectins / immunology*
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Mannose-Binding Lectins / metabolism
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Membrane Glycoproteins / immunology
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Membrane Glycoproteins / metabolism
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Mice
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Mice, Knockout
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Mycobacterium bovis / immunology*
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Mycobacterium tuberculosis / immunology
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Myeloid Differentiation Factor 88 / immunology
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Myeloid Differentiation Factor 88 / metabolism
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Nitric Oxide / immunology
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Nitric Oxide / metabolism
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Receptors, Cell Surface / immunology*
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Receptors, Cell Surface / metabolism
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Receptors, Interleukin-1 / immunology
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Receptors, Interleukin-1 / metabolism
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Signal Transduction / drug effects
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Signal Transduction / immunology
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Toll-Like Receptor 1 / agonists
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Toll-Like Receptor 1 / immunology
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Toll-Like Receptor 2 / agonists
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Toll-Like Receptor 2 / immunology*
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Toll-Like Receptor 2 / metabolism
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Toll-Like Receptor 4 / agonists
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Toll-Like Receptor 4 / immunology
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Toll-Like Receptor 4 / metabolism
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Tumor Necrosis Factor-alpha / immunology*
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Tumor Necrosis Factor-alpha / metabolism
Substances
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Cell Adhesion Molecules
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DC-specific ICAM-3 grabbing nonintegrin
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IL12B protein, human
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Interleukin-12 Subunit p40
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Lectins, C-Type
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Lipopolysaccharides
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MYD88 protein, human
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Mannose Receptor
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Mannose-Binding Lectins
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Membrane Glycoproteins
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Myd88 protein, mouse
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Myeloid Differentiation Factor 88
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Receptors, Cell Surface
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Receptors, Interleukin-1
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TIRAP protein, human
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TIRAP protein, mouse
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TLR2 protein, human
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TLR4 protein, human
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Tlr2 protein, mouse
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Tlr4 protein, mouse
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Toll-Like Receptor 1
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Toll-Like Receptor 2
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Toll-Like Receptor 4
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Tumor Necrosis Factor-alpha
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lipoarabinomannan
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lipomannan
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Nitric Oxide