Mannosylated Lipoarabinomannans Inhibit IL-12 Production by Human Dendritic Cells: Evidence for a Negative Signal Delivered Through the Mannose Receptor

Abstract

IL-12 is a key cytokine in directing the development of type 1 Th cells, which are critical to eradicate intracellular pathogens such as Mycobacterium tuberculosis. Here, we report that mannose-capped lipoarabinomannans (ManLAMs) from Mycobacterium bovis bacillus Calmette-Guérin and Mycobacterium tuberculosis inhibited, in a dose-dependant manner, the LPS-induced IL-12 production by human dendritic cells. The inhibitory activity was abolished by the loss of the mannose caps or the GPI acyl residues. Mannan, which is a ligand for the mannose receptor (MR) as well as an mAb specific for the MR, also inhibited the LPS-induced IL-12 production by dendritic cells. Our results indicate that ManLAMs may act as virulence factors that contribute to the persistence of M. bovis bacillus Calmette-Guérin and M. tuberculosis within phagocytic cells by suppressing IL-12 responses. Our data also suggest that engagement of the MR by ManLAMs delivers a negative signal that interferes with the LPS-induced positive signals delivered by the Toll-like receptors.

Pathogen-Derived Oligosaccharides Improve Innate Immune Response to Intracellular Parasite Infection

“…Based on previous findings described for the treatment of dendritic cells with whole ManLAM, we were interested in determining whether a similar response could be found after the addition of MR blocking antibodies to trimannose-capped bead-treated cells. 23 We found that the addition of MR blocking antibodies recovered IL-12p40 production to a level similar to that observed after TLR2 blocking antibody production (Figure 3), indicating that this may be a response that requires a balance of signaling through both C-type lectin receptors. Based on this diverse range of in vitro macrophage responses to pathogen-derived oligosaccharidecoated beads, we were interested in determining whether these responses would recapitulate when used during in vivo exposure to antigen-presenting cells.…”

“…11 Loss of this oligosaccharide cap from M. bovis bacillus Calmette-Guerin and M. tuberculosis ManLAM was shown to reverse inhibition of LPS-induced IL-12 production by human dendritic cells. 23 We demonstrated the chemical composition and surface availability of these latex bead-bound cap sugars. 19 Given previous results regarding the effect of the larger pathogen glycoconjugates ManLAM and LPG on critical cytokine production by macrophages and dendritic cells, we used novel bead-linked oligosaccharides to determine the role of these five pathogen-derived cap sugars alone in altering in vitro macrophage cytokine production.…”

“…24 -26 A Th1 response is necessary for in vitro and in vivo removal of intracellular Leishmania and Mycobacterium spp. 23,[27][28][29][30] Based on the importance of IL-12 in the in vitro removal of Leishmania and Mycobacterium spp., we tested the ability of CSCBs to drive differential cytokine responses through measurement via ELISA of IL-12p40 production in bead-treated J774 cells. LPS/IFN-␥-stimulated J774 cells exposed to each CSCB induced three alternative responses ( Figure 2, A and B).…”

“…1,31,32 Previous studies have shown that mannose-containing glycolipids induce IL-12 production in a manner different from classical TLR ligands, 33 whereas ManLAM was shown to inhibit the production of IL-12 in human dendritic cells via an MR-dependent mechanism that interfered with TLR-based responses. 23 We examined IL12p40 production after the addition of TLR2 and MR blocking antibodies. The addition of TLR2 blocking antibodies during the treatment of activated J774 cells with trimannose-coated beads eliminated the reduction of IL12p40 production (Figure 3).…”

NADPH oxidase of human dendritic cells: Role in Candida albicans killing and regulation by interferons, dectin‐1 and CD206

“…It is known that DC interact with yeasts essentially by the mannose-binding receptors CD206 [22,31] 32,[34][35][36][37] and TLR2 [32,38,39]. Therefore, we analyzed Candida uptake in the presence of mannan, which binds both CD206 and DC-SIGN [40,41] and interferes with particle internalization by these receptors [42], or laminarin, a specific dectin-1 inhibitor [27,35,40,41,43]. Fig.…”