Neisserial Lipooligosaccharides (LOS) Differentially Modulate Innate Immune Responses in Human Monocytes throughTLR4 Signaling (135.17)

Abstract

Abstract Neisseria gonorrhoeae and N. meningitidis engage innate immune receptors TLR4 and TLR2, as well as TREM1 and TREM2. In this study, we report differential innate immune activation by Neisserial LOS in monocytes. LOS differentially induced proinflammatory mediators TNF-alpha, IL-1 beta, IL-6 and IL-8 in THP1 monocytic cells as well as IL-10, IL-12, IFN-alpha, MIP-1 alpha, MIP-1 beta, and RANTES in human monocytes. Interestingly, while gonococcal LOS was not able to induce GM-CSF in monocytes, GM-CSF expression was enhanced by meningococcal LOS in both THP1 cells and monocytes. In THP1 cells, the induction of TNF-alpha by LOS was inhibited by anti-TLR4 and anti-CD14 antibody, but not by anti-TLR2, suggesting that the TLR4, but not TLR2, was responsible for the induction of cytokines. The ability of LOS to directly activate the TLR4 pathway was demonstrated by using TLR4-MD2 transfected HEK reporter cells, the activation of which was blocked by lipid IVa, a TLR4-MD2 antagonist. In monocytes, lipid IVa also inhibited the induction of all cytokines as well as CD80 expression by gonococcal LOS, but it only inhibited the activation of TNF-alpha, IL-10 and GM-CSF by meningococcal LOS. These results suggest that Neisserial LOS differentially activate innate immunity in monocytes through the TLR4 pathway, but that the induction of innate immune responses by meningococcal LOS may rely on the engagement of additional pattern recognition receptors.