Mycobacterial phosphatidyl inositol mannosides negatively regulate host toll-like receptor 4, MYD88-dependent proinflammatory cytokines and trif-dependent co-stimulatory molecules expression. - Archive ouverte HAL Access content directly
Journal Articles Journal of Biological Chemistry Year : 2009

Mycobacterial phosphatidyl inositol mannosides negatively regulate host toll-like receptor 4, MYD88-dependent proinflammatory cytokines and trif-dependent co-stimulatory molecules expression.

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Abstract

Mycobacterium tuberculosis modulates host immune responses through proteins and complex glycolipids. Here, we report that the GPI anchor phosphatidyl-myo-inositol hexa-mannosides (PIM6) or PIM2 exert potent anti-inflammatory activities. PIM strongly inhibited the Toll-like receptor (TLR) 4, Myeloid Differentiation protein 88 (MyD88)-mediated release of NO, cytokines and chemokines, including TNF, IL-12p40, IL-6, KC, but also IL-10, by LPS-activated macrophages. This effect was independent of the presence of TLR2. PIM also reduced the LPS induced MyD88-independent, TIR-domain-containing adaptor protein inducing IFNgamma (TRIF)-mediated expression of co-stimulatory receptors. PIM inhibited LPS / TLR4-induced NFkappaB translocation. Synthetic PIM1 and a PIM2 mimetic recapitulated these in vitro activities and inhibited endotoxin induced airway inflammation, TNF and KC secretion, and neutrophil recruitment in vivo. Mannosyl, two acyl chains and phosphatidyl residues are essential for PIM anti-inflammatory activity, while the inosityl moiety is dispensable. Therefore, PIM exert potent anti-inflammatory effects both in vitro and in vivo that may contribute to the strategy developed by mycobacteria for repressing the host innate immunity and synthetic PIM analogs represent powerful anti-inflammatory leads.
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hal-00404964 , version 1 (22-03-2021)

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Emilie Doz, Stéphanie Rose, Nathalie Court, Sophie Front, Virginie Vasseur, et al.. Mycobacterial phosphatidyl inositol mannosides negatively regulate host toll-like receptor 4, MYD88-dependent proinflammatory cytokines and trif-dependent co-stimulatory molecules expression.. Journal of Biological Chemistry, 2009, 284, epub ahead of print. ⟨10.1074/jbc.M109.037846⟩. ⟨hal-00404964⟩
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