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

Esen, Nilufer; Kielian, Tammy

doi:10.1016/j.jneuroim.2005.09.003

Cited by 24 publications

(30 citation statements)

References 79 publications

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“…1, all three bacterial stimuli were found to enhance microglial MyD88 protein levels. As we had recently reported, TLR2 protein expression was elevated in response to S. aureus, PGN, and LPS in WT microglia (18,38) (Fig. 2).…”

Section: Quantitative Real-time Rt-pcr (Qrt-pcr)supporting

confidence: 78%

“…In our previous studies, we demonstrated that microglial proinflammatory mediator production was not attenuated in either TLR2 or CD14 KO microglia following S. aureus stimulation, suggesting the activation of alternative receptors (18,38). However, in the present work we have reported that cytokine/chemokine production in MyD88 KO microglia was nearly abolished in response to intact S. aureus.…”

Section: Discussioncontrasting

confidence: 61%

“…Recent studies from our laboratory have demonstrated that, unlike other proinflammatory cytokines examined, IL-12 p40 release was significantly increased in both S. aureus-stimulated TLR2 and CD14 KO microglia compared with WT cells (18,38). Based on these results we had suggested that TLR2 signaling, potentially in cooperation with CD14, regulates IL-12 p40 release by inducing suppressor cytokines and/or activating a direct suppressor pathway.…”

Section: Myd88-dependent Signals Are Pivotal For the Induction Of Promentioning

confidence: 67%

“…Previous studies from our laboratory have revealed that both S. aureus and PGN modulate the expression of alternative PRRs in microglia, including the phagocytic receptors LOX-1 and PTX3 as well as TLR9 (18,38). Because LOX-1 and PTX3 are considered phagocytic receptors and can directly bind pathogens (53-55), they may be responsible for S. aureus uptake by microglia.…”

Section: Role Of Myd88 On the Expression Of Alternative Prrs In Micromentioning

confidence: 97%

“…The experimental procedure was performed as previously described (18). Briefly, TLR2 and GAPDH primers and TAMRA TaqMan probes were designed as previously described (18,38) protein expression in primary microglia was evaluated by Western blotting. As shown in Fig.…”

Section: Quantitative Real-time Rt-pcr (Qrt-pcr)mentioning

confidence: 99%

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Central Role for MyD88 in the Responses of Microglia to Pathogen-Associated Molecular Patterns

Esen

Kielian

2006

The Journal of Immunology

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Microglia, the innate immune effector cells of the CNS parenchyma, express TLR that recognize conserved motifs of microorganisms referred to as pathogen-associated molecular patterns (PAMP). All TLRs identified to date, with the exception of TLR3, use a common adaptor protein, MyD88, to transduce activation signals. Recently, we reported that microglial activation in response to the Gram-positive bacterium Staphylococcus aureus was not completely attenuated following TLR2 ablation, suggesting the involvement of additional receptors. To assess the functional role of alternative TLRs in microglial responses to S. aureus and its cell wall product peptidoglycan as well as the Gram-negative PAMP LPS, we evaluated primary microglia from MyD88 knockout (KO) and wild-type mice. The induction of TNF-α, IL-12 p40, and MIP-2 (CXCL2) expression by S. aureus- and peptidoglycan-stimulated microglia was MyD88 dependent, as revealed by the complete inhibition of cytokine production in MyD88 KO cells. In addition, the expression of additional pattern recognition receptors, including TLR9, pentraxin-3, and lectin-like oxidized LDL receptor-1, was regulated, in part, via a MyD88-dependent manner as demonstrated by the attenuated expression of these receptors in MyD88 KO microglia. Microglial activation was only partially inhibited in LPS-stimulated MyD88 KO cells, suggesting the involvement of MyD88-independent pathways. Collectively, these findings reveal the complex mechanisms for microglia to respond to diverse bacterial pathogens, which occur via both MyD88-dependent and -independent pathways.

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Section: Quantitative Real-time Rt-pcr (Qrt-pcr)supporting

confidence: 78%

Section: Discussioncontrasting

confidence: 61%

Section: Myd88-dependent Signals Are Pivotal For the Induction Of Promentioning

confidence: 67%

Section: Role Of Myd88 On the Expression Of Alternative Prrs In Micromentioning

confidence: 97%

Section: Quantitative Real-time Rt-pcr (Qrt-pcr)mentioning

confidence: 99%

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Central Role for MyD88 in the Responses of Microglia to Pathogen-Associated Molecular Patterns

Esen

Kielian

2006

The Journal of Immunology

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NOD2 plays an important role in the inflammatory responses of microglia and astrocytes to bacterial CNS pathogens

Chauhan

Sterka

Furr

et al. 2008

Glia

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While glial cells are recognized for their roles in maintaining neuronal function, there is growing appreciation that resident central nervous system (CNS) cells initiate and/or augment inflammation following trauma or infection. We have recently demonstrated that microglia and astrocytes constitutively express nucleotide-binding oligomerization domain-2 (NOD2), a member of the novel nucleotide-binding domain leucine-rich repeat region containing family of proteins (NLR) that functions as an intracellular receptor for a minimal motif present in all bacterial peptidoglycans. In the present study, we have confirmed the functional nature of NOD2 expression in astrocytes and microglia and begun to determine the relative contribution that this NLR makes in inflammatory CNS responses to clinically relevant bacterial pathogens. We demonstrate the increased association of NOD2 with its downstream effector molecule, Rip2 kinase, in primary cultures of murine microglia and astrocytes following exposure to bacterial antigens. We show that this cytosolic receptor underlies the ability of muramyl dipeptide to augment the production of inflammatory cytokines by glia following exposure to specific ligands for disparate Toll-like receptor homologues. In addition, we demonstrate that NOD2 is an important component in the in vitro inflammatory responses of resident glia to N. meningitidis and B. burgdorferi antigens. Finally, we have established that NOD2 is required, at least in part, for the astrogliosis, demyelination, behavioral changes, and elevated inflammatory cytokine levels observed following in vivo infection with these pathogens. As such, we have identified NOD2 as an important component in the generation of damaging CNS inflammation following bacterial infection.

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NOD2 mediates inflammatory responses of primary murine glia to Streptococcus pneumoniae

Liu

Chauhan

Young

et al. 2010

Glia

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It is now widely accepted that resident central nervous system (CNS) cells such as microglia and astrocytes initiate and/or augment inflammation following trauma or infection. However, the mechanisms by which glial cells perceive microbial challenges are only now becoming apparent. We have recently demonstrated that microglia and astrocytes constitutively express nucleotide-binding oligomerization domain-2 (NOD2), a member of the novel nucleotide-binding domain leucine-rich repeat region-containing family of proteins (NLR) that functions as an intracellular receptor for a minimal motif present in all bacterial peptidoglycans. Furthermore, we have shown that this NLR is essential for glial responses to Gram-negative pathogens and in vivo CNS inflammation elicited by these organisms. In the present study, we have established that intact Streptococcus pneumoniae, the major causative agent for Gram-positive bacterial meningitis in adults, is a potent stimulus for the activation of the pivotal inflammatory transcription factor NF-kB and production of inflammatory cytokines in primary murine microglia and astrocytes. We demonstrate that NOD2 is essential for the maximal responses of these cells to intact S. pneumoniae but not cellular lysates. Finally, we have shown that this cytosolic pattern recognition receptor is required for the elevated inflammatory mediator levels, astrogliosis, and demyelination, following in vivo administration of this Gram-positive CNS pathogen. As such, we suggest that NOD2 plays a critical role in the establishment of the lethal inflammation associated with streptococcal meningitis.

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

Cited by 24 publications

References 79 publications

Central Role for MyD88 in the Responses of Microglia to Pathogen-Associated Molecular Patterns

Central Role for MyD88 in the Responses of Microglia to Pathogen-Associated Molecular Patterns

NOD2 plays an important role in the inflammatory responses of microglia and astrocytes to bacterial CNS pathogens

NOD2 mediates inflammatory responses of primary murine glia to Streptococcus pneumoniae

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