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Implicating Receptor Activator of NF-κB (RANK)/ RANK Ligand Signalling in Microglial Responses to Toll-Like Receptor Stimuli

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Implicating Receptor Activator of NF-κB (RANK)/ RANK Ligand Signalling in Microglial Responses to Toll-Like Receptor Stimuli. / Kichev, Anton; Eede, Pascale; Gressens, Pierre; Thornton, Claire; Hagberg, Erik Gustaf Henrik.

In: Developmental Neuroscience, 13.04.2017.

Research output: Contribution to journalArticle

Harvard

Kichev, A, Eede, P, Gressens, P, Thornton, C & Hagberg, EGH 2017, 'Implicating Receptor Activator of NF-κB (RANK)/ RANK Ligand Signalling in Microglial Responses to Toll-Like Receptor Stimuli', Developmental Neuroscience. https://doi.org/10.1159/000464244

APA

Kichev, A., Eede, P., Gressens, P., Thornton, C., & Hagberg, E. G. H. (2017). Implicating Receptor Activator of NF-κB (RANK)/ RANK Ligand Signalling in Microglial Responses to Toll-Like Receptor Stimuli. Developmental Neuroscience. https://doi.org/10.1159/000464244

Vancouver

Kichev A, Eede P, Gressens P, Thornton C, Hagberg EGH. Implicating Receptor Activator of NF-κB (RANK)/ RANK Ligand Signalling in Microglial Responses to Toll-Like Receptor Stimuli. Developmental Neuroscience. 2017 Apr 13. https://doi.org/10.1159/000464244

Author

Kichev, Anton ; Eede, Pascale ; Gressens, Pierre ; Thornton, Claire ; Hagberg, Erik Gustaf Henrik. / Implicating Receptor Activator of NF-κB (RANK)/ RANK Ligand Signalling in Microglial Responses to Toll-Like Receptor Stimuli. In: Developmental Neuroscience. 2017.

Bibtex Download

@article{5909050f4a0a48f69dccfb6059e4644d,
title = "Implicating Receptor Activator of NF-κB (RANK)/ RANK Ligand Signalling in Microglial Responses to Toll-Like Receptor Stimuli",
abstract = "Inflammation in the perinatal brain caused by maternal or intrauterine fetal infection is now well established as an important contributor to the development of perinatal brain injury. Exposure to inflammatory products can impair perinatal brain development and act as a risk factor for neurological dysfunction, cognitive disorders, cerebral palsy, or preterm birth. Pre-exposure to inflammation significantly exacerbates brain injury caused by hypoxic/ischaemic insult. Tumour necrosis factor (TNF) is a family of cytokines largely involved in inflammation signalling. In our previous study, we identified the importance of TNF-related apoptosis-inducing ligand (TRAIL) signalling in the development of perinatal brain injury. We observed a significant increase in the expression levels of a soluble decoy receptor for TRAIL, osteoprotegerin (OPG). Besides TRAIL, OPG is able to bind the receptor activator of the NF-κB (RANK) ligand (RANKL) and inhibit its signalling. The function of the RANK/RANKL/OPG system in the brain has not come under much scrutiny. The aim of this research study was to elucidate the role of RANK, RANKL, and OPG in microglial responses to the proinflammatory stimuli lipopolysaccharide (LPS) and polyinosinic-polycytidylic acid (Poly I:C). Here, we show that RANK signalling is important for regulating the activation of the BV2 microglial cell line. We found that LPS treatment causes a significant decrease in the expression of RANK in the BV2 cell line while significantly increasing the expression of OPG, Toll-like receptor (TLR)3, and the adaptor proteins MyD88 and TRIF. We found that pretreatment of BV2 cells with RANKL for 24 h before the LPS or Poly I:C exposure decreases the expression of inflammatory markers such as inducible nitric oxide synthase and cyclooxygenase. This is accompanied by a decreased expression of the TLR adaptor proteins MyD88 and TRIF, which we observed after RANKL treatment. Similar results were obtained in our experiments with primary mouse microglia. Using recently developed CRISPR/Cas9 technology, we generated a BV2 cell line lacking RANK (RANK-/- BV2). We showed that most effects of RANKL pretreatment were abolished, thereby proving the specificity of this effect. Taken together, these findings suggest that RANK signalling is important for modulating the inflammatory activation of microglial cells to a moderate level, and that RANK attenuates TLR3/TLR4 signalling.",
author = "Anton Kichev and Pascale Eede and Pierre Gressens and Claire Thornton and Hagberg, {Erik Gustaf Henrik}",
year = "2017",
month = "4",
day = "13",
doi = "10.1159/000464244",
language = "English",
journal = "Developmental Neuroscience",
issn = "0378-5866",
publisher = "S. Karger AG",

}

RIS (suitable for import to EndNote) Download

TY - JOUR

T1 - Implicating Receptor Activator of NF-κB (RANK)/ RANK Ligand Signalling in Microglial Responses to Toll-Like Receptor Stimuli

AU - Kichev, Anton

AU - Eede, Pascale

AU - Gressens, Pierre

AU - Thornton, Claire

AU - Hagberg, Erik Gustaf Henrik

PY - 2017/4/13

Y1 - 2017/4/13

N2 - Inflammation in the perinatal brain caused by maternal or intrauterine fetal infection is now well established as an important contributor to the development of perinatal brain injury. Exposure to inflammatory products can impair perinatal brain development and act as a risk factor for neurological dysfunction, cognitive disorders, cerebral palsy, or preterm birth. Pre-exposure to inflammation significantly exacerbates brain injury caused by hypoxic/ischaemic insult. Tumour necrosis factor (TNF) is a family of cytokines largely involved in inflammation signalling. In our previous study, we identified the importance of TNF-related apoptosis-inducing ligand (TRAIL) signalling in the development of perinatal brain injury. We observed a significant increase in the expression levels of a soluble decoy receptor for TRAIL, osteoprotegerin (OPG). Besides TRAIL, OPG is able to bind the receptor activator of the NF-κB (RANK) ligand (RANKL) and inhibit its signalling. The function of the RANK/RANKL/OPG system in the brain has not come under much scrutiny. The aim of this research study was to elucidate the role of RANK, RANKL, and OPG in microglial responses to the proinflammatory stimuli lipopolysaccharide (LPS) and polyinosinic-polycytidylic acid (Poly I:C). Here, we show that RANK signalling is important for regulating the activation of the BV2 microglial cell line. We found that LPS treatment causes a significant decrease in the expression of RANK in the BV2 cell line while significantly increasing the expression of OPG, Toll-like receptor (TLR)3, and the adaptor proteins MyD88 and TRIF. We found that pretreatment of BV2 cells with RANKL for 24 h before the LPS or Poly I:C exposure decreases the expression of inflammatory markers such as inducible nitric oxide synthase and cyclooxygenase. This is accompanied by a decreased expression of the TLR adaptor proteins MyD88 and TRIF, which we observed after RANKL treatment. Similar results were obtained in our experiments with primary mouse microglia. Using recently developed CRISPR/Cas9 technology, we generated a BV2 cell line lacking RANK (RANK-/- BV2). We showed that most effects of RANKL pretreatment were abolished, thereby proving the specificity of this effect. Taken together, these findings suggest that RANK signalling is important for modulating the inflammatory activation of microglial cells to a moderate level, and that RANK attenuates TLR3/TLR4 signalling.

AB - Inflammation in the perinatal brain caused by maternal or intrauterine fetal infection is now well established as an important contributor to the development of perinatal brain injury. Exposure to inflammatory products can impair perinatal brain development and act as a risk factor for neurological dysfunction, cognitive disorders, cerebral palsy, or preterm birth. Pre-exposure to inflammation significantly exacerbates brain injury caused by hypoxic/ischaemic insult. Tumour necrosis factor (TNF) is a family of cytokines largely involved in inflammation signalling. In our previous study, we identified the importance of TNF-related apoptosis-inducing ligand (TRAIL) signalling in the development of perinatal brain injury. We observed a significant increase in the expression levels of a soluble decoy receptor for TRAIL, osteoprotegerin (OPG). Besides TRAIL, OPG is able to bind the receptor activator of the NF-κB (RANK) ligand (RANKL) and inhibit its signalling. The function of the RANK/RANKL/OPG system in the brain has not come under much scrutiny. The aim of this research study was to elucidate the role of RANK, RANKL, and OPG in microglial responses to the proinflammatory stimuli lipopolysaccharide (LPS) and polyinosinic-polycytidylic acid (Poly I:C). Here, we show that RANK signalling is important for regulating the activation of the BV2 microglial cell line. We found that LPS treatment causes a significant decrease in the expression of RANK in the BV2 cell line while significantly increasing the expression of OPG, Toll-like receptor (TLR)3, and the adaptor proteins MyD88 and TRIF. We found that pretreatment of BV2 cells with RANKL for 24 h before the LPS or Poly I:C exposure decreases the expression of inflammatory markers such as inducible nitric oxide synthase and cyclooxygenase. This is accompanied by a decreased expression of the TLR adaptor proteins MyD88 and TRIF, which we observed after RANKL treatment. Similar results were obtained in our experiments with primary mouse microglia. Using recently developed CRISPR/Cas9 technology, we generated a BV2 cell line lacking RANK (RANK-/- BV2). We showed that most effects of RANKL pretreatment were abolished, thereby proving the specificity of this effect. Taken together, these findings suggest that RANK signalling is important for modulating the inflammatory activation of microglial cells to a moderate level, and that RANK attenuates TLR3/TLR4 signalling.

U2 - 10.1159/000464244

DO - 10.1159/000464244

M3 - Article

JO - Developmental Neuroscience

JF - Developmental Neuroscience

SN - 0378-5866

ER -

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