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.

Details

Serval ID
serval:BIB_1244E4834063
Type
Article: article from journal or magazin.
Collection
Publications
Title
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.
Journal
FASEB journal
Author(s)
Volz T., Nega M., Buschmann J., Kaesler S., Guenova E., Peschel A., Röcken M., Götz F., Biedermann T.
ISSN
1530-6860 (Electronic)
ISSN-L
0892-6638
Publication state
Published
Issued date
10/2010
Peer-reviewed
Oui
Volume
24
Number
10
Pages
4089-4102
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
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 (PGN(polymer)) preparations activated NF-κB 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, PGN(polymer) from lgt-mutant S. aureus failed to stimulate human TLR2, demonstrating that lipoproteins within the macromolecular structures of PGN(polymer), but not PGN itself, activate TLR2. Thus, HPLC-purified monomeric PGN (PGN(monomer)) structures were investigated. Strikingly, PGN(monomer) completely lacked NF-κB activation, lacked TLR2 activity, and failed to functionally activate murine DCs. However, PGN(monomer) 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 PGN(monomer) markedly up-regulated Th1 and Th17 while suppressing Th2 cell priming. Notably, PGN(monomer) failed to coactivate NOD2(-/-) DCs. This demonstrates that PGN(monomer) 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 PGN(monomer), 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.
Keywords
Animals, Base Sequence, Chromatography, High Pressure Liquid, DNA Primers, Dendritic Cells/immunology, Flow Cytometry, Humans, Immunity, Innate, Mice, Mice, Inbred C57BL, Nod2 Signaling Adaptor Protein/metabolism, Peptidoglycan/metabolism, Staphylococcus aureus/metabolism, Toll-Like Receptors/metabolism
Pubmed
Web of science
Create date
27/08/2020 14:00
Last modification date
02/09/2020 5:26
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