title: Mycobacterial PIMs inhibit host inflammatory responses through CD14-dependent and CD14-independent mechanisms.
abstract: Mycobacteria develop strategies to evade the host immune system. Among them, mycobacterial LAM or PIMs inhibit the expression of pro-inflammatory cytokines by activated macrophages. Here, using synthetic PIM analogues, we analyzed the mode of action of PIM anti-inflammatory effects. Synthetic PIM(1) isomer and PIM(2) mimetic potently inhibit TNF and IL-12 p40 expression induced by TLR2 or TLR4 pathways, but not by TLR9, in murine macrophages. We show inhibition of LPS binding to TLR4/MD2/CD14 expressing HEK cells by PIM(1) and PIM(2) analogues. More specifically, the binding of LPS to CD14 was inhibited by PIM(1) and PIM(2) analogues. CD14 was dispensable for PIM(1) and PIM(2) analogues functional inhibition of TLR2 agonists induced TNF, as shown in CD14-deficient macrophages. The use of rough-LPS, that stimulates TLR4 pathway independently of CD14, allowed to discriminate between CD14-dependent and CD14-independent anti-inflammatory effects of PIMs on LPS-induced macrophage responses. PIM(1) and PIM(2) analogues inhibited LPS-induced TNF release by a CD14-dependent pathway, while IL-12 p40 inhibition was CD14-independent, suggesting that PIMs have multifold inhibitory effects on the TLR4 signalling pathway.
authors.affiliation: University of Orléans Molecular Immunology and Embryology, Orléans, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Court
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Rose
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Bourigault
authors.forename: Sophie
authors.initials: S
authors.lastname: Front
authors.forename: Olivier R
authors.initials: OR
authors.lastname: Martin
authors.forename: Jennifer K
authors.initials: JK
authors.lastname: Dowling
authors.forename: Elaine F
authors.initials: EF
authors.lastname: Kenny
authors.forename: Luke
authors.initials: L
authors.lastname: O'Neill
authors.forename: François
authors.initials: F
authors.lastname: Erard
authors.forename: Valerie F J
authors.initials: VF
authors.lastname: Quesniaux
mesh_terms: D000215:Acylation / Q000187:drug effects; D000818:Animals; D057809:HEK293 Cells; D054884:Host-Pathogen Interactions / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D007249:Inflammation / Q000276:immunology* / Q000382:microbiology* / Q000473:pathology; D018664:Interleukin-12 / Q000378:metabolism; D018950:Lipopolysaccharide Receptors / Q000276:immunology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008362:Mannosides / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009161:Mycobacterium / Q000187:drug effects / Q000276:immunology*; D017239:Paclitaxel / Q000737:chemistry / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D012995:Solubility / Q000187:drug effects; D013501:Surface-Active Agents / Q000494:pharmacology; D051193:Toll-Like Receptors / Q000819:agonists / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D008362:Mannosides; D013501:Surface-Active Agents; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D017239:Paclitaxel