Primate Monocytes - CD14, CD16 - Ziegler-Heitbrock

Natural Staphylococcus aureus-derived peptidoglycan fragments activate NOD2 and act as potent costimulators of the innate immune system exclusively in the presence of TLR signals.

Abstract

Innate immune sensing of Staphylococcus aureus unravels basic mechanisms leading to either effective antibacterial immune responses or harmful inflammation. The nature and properties of S. aureus-derived pathogen-associated molecular pattern (PAMPs) are still not completely understood. We investigated the innate immune sensing of peptidoglycan (PGN) structures and subsequent immune consequences. Macromolecular PGN (PGNpolymer) preparations activated NF-kappaB through human Toll-like receptors 2 (TLR2), as shown by luciferase reporter assays, and induced murine dendritic cell (DC) maturation and cytokine production. In contrast, PGNpolymer from lgt-mutant S. aureus failed to stimulate human TLR2, demonstrating that lipoproteins within the macromolecular structures of PGNpolymer, but not PGN itself, activate TLR2. Thus, HPLC-purified monomeric PGN (PGNmonomer) structures were investigated. Strikingly, PGNmonomer completely lacked NF-kappaB activation, lacked TLR2 activity, and failed to functionally activate murine DCs. However, PGNmonomer in concert with various TLR ligands most effectively stimulated DCs to up-regulate IL-12p70 and IL-23 by >/=3- to 5-fold. Consequently, DCs coactivated by PGNmonomer markedly up-regulated Th1 and Th17 while suppressing Th2 cell priming. Notably, PGNmonomer failed to coactivate NOD2(-/-) DCs. This demonstrates that PGNmonomer is a natural ligand of NOD2, which was previously only demonstrated for synthetic compounds like muramyl dipeptide. Interestingly, murine DCs lacking TLR2 remained mute in response to the combinative immune sensing of S. aureus-derived PAMPs, including PGNmonomer, providing for the first time an explanation of why S. aureus can colonize the nasal mucosa in the absence of inflammation. This is very likely based on the lack of TLR2 expression in mucosal epithelial cells under normal conditions, which determines the unresponsiveness to S. aureus PAMPs.-Volz, T., Nega, M., Buschmann, J., Kaesler, S., Guenova, E., Peschel, A., Röcken, M., Götz, F., Biedermann, T. Natural Staphylococcus aureus-derived peptidoglycan fragments activate NOD2 and act as potent costimulator of the innate immune system exclusively in the presence of TLR signals.