Mycobacterial PIMs inhibit host inflammatory responses through CD14-dependent and CD14-independent mechanisms

Nathalie Court, Stéphanie Rose, Marie Laure Bourigault, Sophie Front, Olivier R. Martin, Jennifer K. Dowling, Elaine F. Kenny, Luke O'Neill, François Erard, Valerie F J Quesniaux

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18 Citations (Scopus)

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.

Original languageEnglish
Article numbere24631
Number of pages12
JournalPLoS ONE
Volume6
Issue number9
DOIs
Publication statusPublished - 16 Sep 2011
Externally publishedYes

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