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.
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.
Doz
Emilie
E
Orleans University and CNRS, Molecular Immunology and Embryology, UMR6218, 45071 Orléans, France.
Rose
Stéphanie
S
Nigou
Jérôme
J
Gilleron
Martine
M
Puzo
Germain
G
Erard
François
F
Ryffel
Bernhard
B
Quesniaux
Valerie F J
VF
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
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