Peptidoglycan- and Lipoteichoic Acid-induced Cell Activation Is Mediated by Toll-like Receptor 2

Schwandner, Ralf; Dziarski, Roman; Wesche, Holger; Rothe, Mike; Kirschning, Carsten J.

doi:10.1074/jbc.274.25.17406

Cited by 1,524 publications

(1,205 citation statements)

References 38 publications

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“…Since TLR2 and CD14 have been reported to cooperate in mediating macrophage activation in response to gram-positive stimuli (Medvedev et al, 1998;Schwandner et al, 1999;Yoshimura et al, 1999), we examined whether a similar phenomenon occurs in CD14 KO microglia. Similar to our findings with TLR2 KO microglia, IL-12 p40 production was consistently elevated in CD14 KO microglia in response to S. aureus compared to WT cells (Fig.…”

Section: Cd14 Differentially Regulates Pgn and S Aureus Recognition mentioning

confidence: 99%

“…In addition, upon exposure to S. aureus and PGN, microglia respond with the robust synthesis and release of numerous proinflammatory mediators as well as internalizing and killing S. aureus in vitro (Kielian et al, 2002(Kielian et al, , 2005. Although previous studies have demonstrated that PGN binds to CD14 and enhances TLR2-mediated signaling in macrophages (Iwaki et al, 2002;Koedel et al, 2003;Schwandner et al, 1999), the fundamental role of CD14 in S. aureus-and PGNdependent microglial activation is not known. In the current study, we evaluated the relative importance of CD14 on S. aureus and PGN recognition using primary microglia isolated from CD14 KO and WT mice.…”

Section: Introductionmentioning

confidence: 99%

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Recognition of Staphylococcus aureus-derived peptidoglycan (PGN) but not intact bacteria is mediated by CD14 in microglia

Esen

Kielian

2005

Journal of Neuroimmunology

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Recognition of Staphylococcus aureus and its cell-wall component peptidoglycan (PGN) by microglia is mediated, in part, by Toll-like receptor 2 (TLR2). However, the pattern recognition receptor (PRR) CD14 can also bind PGN and enhance TLR2-mediated signaling in macrophages, suggesting a similar phenomenon might occur in microglia. To assess the functional significance of CD14 on microglial activation, we evaluated the responses of primary microglia isolated from CD14 knockout (KO) and wild type (WT) mice. PGN-dependent microglial activation was partially CD14-dependent as demonstrated by the attenuated expression of TNF-α, macrophage inflammatory protein-2 (MIP-2/CXCL2), and the soluble PRR pentraxin-3 in CD14 KO microglia compared to WT cells. In contrast, microglial responses to intact S. aureus occurred primarily via a CD14-independent manner. Collectively, these findings reveal the complex nature of gram-positive bacterial recognition by microglia, which occurs, in part, via CD14.

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Section: Cd14 Differentially Regulates Pgn and S Aureus Recognition mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Recognition of Staphylococcus aureus-derived peptidoglycan (PGN) but not intact bacteria is mediated by CD14 in microglia

Esen

Kielian

2005

Journal of Neuroimmunology

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“…As members of an evolutionary ancient first-line defence system, TLR detect the presence of conserved pathogen-associated molecular patterns (PAMP), which are produced by microorganisms. While lipopolysaccharide (LPS) signals mainly through TLR4 [4], TLR2 binds peptidoglycan, lipoteichoic acid (LTA), yeast-particle zymosan and the glycosylphosphatidylinositol anchor of Trypanosoma cruzi [5,6]. Moreover, binding of LPS is facilitated through the lipid-binding, glycosylphosphatidylinositolanchored membrane protein CD14 [7,8].…”

Section: Introductionmentioning

confidence: 99%

Vitamin D3 down‐regulates monocyte TLR expression and triggers hyporesponsiveness to pathogen‐associated molecular patterns

et al. 2006

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Toll-like receptors (TLR) represent an ancient front-line defence system that enables the host organism to sense the presence of microbial components within minutes. As inducers of inflammation, TLR act as important triggers of distinct entities such as sepsis or autoimmune disease exacerbation. We report here that vitamin D3 [1a,25-dihydroxycholecalciferol, 1,25(OH) 2 D3] suppresses the expression of TLR2 and TLR4 protein and mRNA in human monocytes in a time-and dose-dependent fashion. Despite 1,25(OH) 2 D3-induced up-regulation of CD14, challenge of human monocytes with either LPS or lipoteichoic acid resulted in impaired TNF-a and procoagulatory tissue factor (CD142) production, emphasizing the critical role of TLR in the induction of inflammation. Moreover, reduced TLR levels in 1,25(OH) 2 D3-treated phagocytes were accompanied by impaired NF-jB/RelA translocation to the nucleus and by reduced p38 and p42/44 (extracellular signal-regulated kinase 1/2) phosphorylation upon TLRligand engagement. Both TLR down-regulation and CD14 up-regulation were substantially inhibited by the vitamin D receptor (VDR) antagonist ZK 159222, indicating that the immunomodulatory effect of 1,25(OH) 2 D3 on innate immunity receptors requires VDR transcription factor activation. Our data provide strong evidence that 1,25(OH) 2 D3 primes monocytes to respond less effectively to bacterial cell wall components in a VDR-dependent mechanism, most likely due to decreased levels of TLR2 and TLR4.

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“…These TLRs play a key role in the recognition of microbe-associated molecular patterns from Gram-positive and Gram-negative bacterial species. TLR2 is activated by bacterial lipoproteins, lipoteichoic acid, and, in conjunction with TLR1 or TLR6, by diacylated or triacylated lipopeptides, respectively (Aliprantis et al, 1999;Schwandner et al, 1999). TLR4 can form a complex with MD-2 and CD14 and signals the presence of bacterial lipopolysaccharide (LPS) (Hoshino et al, 1999;Poltorak et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

Ligand-induced differential cross-regulation of Toll-like receptors 2, 4 and 5 in intestinal epithelial cells

Aubel

Keestra

Krooshoop

et al. 2007

Molecular Immunology

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Toll-like receptors (TLR) 2, TLR4 and TLR5 are primary mucosal sensors of microbial patterns. Dissection of the cross-talk between TLRs in intestinal cells has thus far been hampered by the lack of functional TLR2 and TLR4 in in vitro model systems. Here we report that the mouse intestinal epithelial cell line mIC cl2 expresses these TLRs and that receptor expression and function are regulated by environmental TLR stimuli. Our results show that stimulation of TLR5 by bacterial flagellin resulted in upregulated TLR2 and TLR4 mRNA and concomitant sensitization of the cells for subsequent TLR2 (Pam 3 CSK 4 ) and TLR4 (LPS) stimulation. Exposure to low amounts of either Pam 3 CSK 4 or LPS in turn downregulated TLR5 mRNA and attenuated subsequent flagellin-mediated NF-B activation, pointing to a negative feedback mechanism. Pam 3 CSK 4 and LPS also downregulated TLR4 mRNA but upregulated TLR2 mRNA and sensitized cells for subsequent TLR2 stimulation. Inhibition of the phosphatidylinositol-3-kinase/Akt pathway only affected LPS-mediated TLR cross-talk indicating that differential TLR cross-regulation was conferred via different mechanisms. Together, our results demonstrate that the expression and function of TLR in intestinal cells are highly dynamic and tightly regulated in response to encountered bacterial stimuli.

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Peptidoglycan- and Lipoteichoic Acid-induced Cell Activation Is Mediated by Toll-like Receptor 2

Cited by 1,524 publications

References 38 publications

Recognition of Staphylococcus aureus-derived peptidoglycan (PGN) but not intact bacteria is mediated by CD14 in microglia

Recognition of Staphylococcus aureus-derived peptidoglycan (PGN) but not intact bacteria is mediated by CD14 in microglia

Vitamin D3 down‐regulates monocyte TLR expression and triggers hyporesponsiveness to pathogen‐associated molecular patterns

Ligand-induced differential cross-regulation of Toll-like receptors 2, 4 and 5 in intestinal epithelial cells

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