Nod2 Downregulates TLR2/1 Mediated IL1β Gene Expression in Mouse Peritoneal Macrophages

Dahiya, Yogesh; Pandey, R. K.; Sodhi, Ajit

doi:10.1371/journal.pone.0027828

Cited by 16 publications

(14 citation statements)

References 26 publications

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“…Although Gefitinib also suppresses EGFR signaling, taking all the data together, it is likely that NOD2 signaling (perhaps together with EGFR) suppresses production of at least a few chemokines and/or cytokines, perhaps to control inflammation mediated through TLRs. In fact, NOD2 has been shown to inhibit TLR2-mediated signaling in other studies [ 43 , 44 ], indicating that this possibility is viable. In one study, when splenocytes from NOD2-deficient mice were stimulated with peptidoglycan (PGN), a TLR2 ligand, the cytokine production was found to be higher than those from wild-type mice [ 44 ].…”

Section: Discussionmentioning

confidence: 96%

Inflammatory mediator release from primary rhesus microglia in response to Borrelia burgdorferi results from the activation of several receptors and pathways

Parthasarathy

Philipp

2015

J Neuroinflammation

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BackgroundIn previous studies, neurons were documented to undergo apoptosis in the presence of microglia and live Borrelia burgdorferi, but not with either agent alone. Microscopy showed that several Toll-like receptors (TLRs) were upregulated in microglia upon B. burgdorferi exposure. It was hypothesized that the inflammatory milieu generated by microglia in the presence of B. burgdorferi results in neuronal apoptosis and that this inflammation was likely generated through TLR pathways.MethodsIn this study, we explored the role of several TLR and nucleotide-binding oligomerization domain containing 2 (NOD2)-dependent pathways in inducing inflammation in the presence of B. burgdorferi, using ribonucleic acid interference (RNAi) and/or inhibitors, in primary non-human primate (NHP) microglia. We also used several inhibitors for key mitogen-activated protein kinase (MAPK) pathways to determine the role of downstream pathways in inflammatory mediator release.ResultsThe results show that the TLR2 pathway plays a predominant role in inducing inflammation, as inhibition of TLR2 with either small interfering RNA (siRNA) or inhibitor, in the presence of B. burgdorferi, significantly downregulated interleukin 6 (IL-6), chemokine (C-X-C) motif ligand 8 (CXCL8), chemokine (C-C) motif ligand 2 (CCL2), and tumor necrosis factor (TNF) production. This was followed by TLR5, the silencing of which significantly downregulated IL-6 and TNF. The role of TLR4 was inconclusive as a TLR4-specific inhibitor and TLR4 siRNA had opposing effects in the presence of B. burgdorferi. Silencing of NOD2 by siRNA in the presence of B. burgdorferi significantly upregulated IL-6, CCL2, and TNF. Downstream signaling involved the adaptor molecule myeloid differentiation primary response 88 (MyD88), as expected, as well as the MAPK pathways, with extracellular signal-regulated kinase (ERK) being predominant, followed by Jun N-terminal kinase (JNK) and p38 pathways.ConclusionsSeveral receptors and pathways, with both positive and negative effects, mediate inflammation of primary microglia in response to B. burgdorferi, resulting in a complex, tightly regulated immune network.

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Section: Discussionmentioning

confidence: 96%

Inflammatory mediator release from primary rhesus microglia in response to Borrelia burgdorferi results from the activation of several receptors and pathways

Parthasarathy

Philipp

2015

J Neuroinflammation

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“…This usually implies inhibitory effects of NOD2 on TLR‐induced responses. In settings of simultaneous stimulus application, MDP at a concentration of 10 μg/ml has been reported to down‐regulate IL‐1β expression induced by a TLR2/1 agonist (peptidoglycan) in murine peritoneal macrophages in vitro; in the same study, MDP did not affect IL‐1β production induced by LPS (which was used at a high concentration of 1 μg/ml) and up‐regulated TLR2‐induced IL‐10 and TNF production . Watanabe et al.…”

Section: Descriptive Data On Nod‐tlr Interactionsmentioning

confidence: 90%

“…In settings of simultaneous stimulus application, MDP at a concentration of 10 g/ml has been reported to down-regulate IL-1 expression induced by a TLR2/1 agonist (peptidoglycan) in murine peritoneal macrophages in vitro; in the same study, MDP did not affect IL-1 production induced by LPS (which was used at a high concentration of 1 g/ml) and up-regulated TLR2-induced IL-10 and TNF production. 36 Watanabe et al reported that in murine splenic macrophages in vitro, MDP at 10-100 g/ml specifically down-regulated IL-12 production induced through TLR2 but not through several other TLRs. 37 To reconcile conflicting data about positive and negative effects of MDP on TLR-mediated activation, Borm et al showed that MDP at low concentrations (1-25 g/ml) augments TLR2-induced TNF production by monocytes, but at a high concentration (100 g/ml) suppresses it.…”

Section: Nod-tlr Antagonism and Cross-tolerancementioning

confidence: 99%

Synergistic interactions between NOD receptors and TLRs: Mechanisms and clinical implications

Pashenkov

Murugina

Будихина

et al. 2018

Journal of Leukocyte Biology

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Interactions between pattern recognition receptors (PRRs) shape innate immune responses to particular classes of pathogens. Here, we review interactions between TLRs and nucleotide‐binding oligomerization domain 1 and 2 (NOD1 and NOD2) receptors, two major groups of PRRs involved in innate recognition of bacteria. Most of experimental data both in vitro and in vivo suggest that NODs and TLRs synergize with each other at inducing the production of cytokines and antimicrobial peptides. Molecular mechanisms of this synergy remain poorly understood, although several scenarios can be proposed: (i) direct interactions of signaling pathways downstream of NODs and TLRs; (ii) mutual transcriptional regulation of unique components of NOD‐dependent and TLR‐dependent signaling pathways; and (iii) interactions at the post‐transcriptional level. Potential practical implications of NOD‐TLR synergy are dual. In sepsis, where synergistic effects probably contribute to excessive proinflammatory cytokine production, blockade of NOD1, and/or NOD2 in addition to TLR4 blockade may be required to achieve therapeutic benefit. On the other hand, synergistic combinations of relatively small doses of NOD and TLR agonists administered before infection could be used to boost innate resistance against bacterial pathogens.

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“…In agreement with our results, recent studies showed a synergic effect between NOD2 and TLR2 [48], where specific NOD2 activation with MDP increased the induction of TNFα, IL-1 and IL-10 upon co-stimulation with TLR2 agonists. Other studies showed that the activation of NOD2 could modify the expression of TLR2 negatively, although this seems to be determined by the different kinds of studied cells [49]. However, it seems that NOD2 could also recognize the specific bacterial fragments recognized by TLR2 heterodimers (TLR2/1 and TLR2/6) [50].…”

Section: Discussionmentioning

confidence: 98%

NOD2 Modulates Serotonin Transporter and Interacts with TLR2 and TLR4 in Intestinal Epithelial Cells

Layunta

Latorre

Forcén

et al. 2018

Cell Physiol Biochem

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Background/Aims: Serotonin (5-HT) is a chief modulator of intestinal activity. The effects of 5-HT depend on its extracellular availability, which is mainly controlled by serotonin transporter (SERT), expressed in enterocytes. On the other hand, innate immunity, mediated by Toll-like receptors (TLRs) and nucleotide oligomerization domain (NOD)-like receptors (NLRs), is known to control intestinal microbiota and maintain intestinal homeostasis. The dysregulation of the intestinal serotonergic system and innate immunity has been observed in inflammatory bowel diseases (IBD), the incidence of which has severely increased all over the world. The aim of the present study, therefore, was to analyze the effect of NOD2 on intestinal SERT activity and expression, as well as to study the crosstalk of NOD2 with TLR2 and TLR4. Methods: Intestinal epithelial cell line Caco-2/TC7 was used to analyze SERT activity and SERT, NOD2, TLR2 and TLR4 molecular expression by real-time PCR and western blotting. Moreover, intestinal tract (ileum and colon) from mice deficient in TLR2, TLR4 or TLR2/4 receptors was used to test the interdependence of NOD2 with these TLR receptors. Results: NOD2 activation inhibits SERT activity in Caco-2/TC7 cells, mainly due to the decrement of SERT molecular expression, with RIP2/RICK being the intracellular pathway involved in this effect. This inhibitory effect on SERT would yield an increment of extracellular 5-HT availability. In this sense, 5-HT strongly inhibits NOD2 expression. In addition, NOD2 showed greater interdependence with TLR2 than with TLR4. Indeed, NOD2 expression significantly increased in both cells treated with TLR2 agonists and the intestinal tract of Tlr2-/- mice. Conclusions: It may be inferred from our data that NOD2 could play a role in intestinal pathophysiology not only through its inherent innate immune role but also due to its interaction with other receptors as TLR2 and the modulation of the intestinal serotonergic system decreasing SERT activity and expression.

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Nod2 Downregulates TLR2/1 Mediated IL1β Gene Expression in Mouse Peritoneal Macrophages

Cited by 16 publications

References 26 publications

Inflammatory mediator release from primary rhesus microglia in response to Borrelia burgdorferi results from the activation of several receptors and pathways

Inflammatory mediator release from primary rhesus microglia in response to Borrelia burgdorferi results from the activation of several receptors and pathways

Synergistic interactions between NOD receptors and TLRs: Mechanisms and clinical implications

NOD2 Modulates Serotonin Transporter and Interacts with TLR2 and TLR4 in Intestinal Epithelial Cells

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