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Isolation of Cortical Microglia with Preserved Immunophenotype and Functionality From Murine Neonates
Published on: January 30, 2014
Microglial TonEBP mediates LPS-induced inflammation and memory loss as transcriptional cofactor for NF-κB and AP-1
Gyu Won Jeong1, Hwan Hee Lee1, Whaseon Lee-Kwon1
1School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan, 44919, Republic of Korea.
Background:
Microglia are brain-resident myeloid cells involved in the innate immune response and a variety of neurodegenerative diseases. In macrophages, TonEBP is a transcriptional cofactor of NF-κB which stimulates the transcription of pro-inflammatory genes in response to LPS. Here, we examined the role of microglial TonEBP.
Methods:
We used microglial cell line, BV2 cells. TonEBP was knocked down using lentiviral transduction of shRNA. In animals, TonEBP was deleted from myeloid cells using a line of mouse with floxed TonEBP. Cerulenin was used to block the NF-κB cofactor function of TonEBP.
Results:
TonEBP deficiency blocked the LPS-induced expression of pro-inflammatory cytokines and enzymes in association with decreased activity of NF-κB in BV2 cells. We found that there was also a decreased activity of AP-1 and that TonEBP was a transcriptional cofactor of AP-1 as well as NF-κB. Interestingly, we found that myeloid-specific TonEBP deletion blocked the LPS-induced microglia activation and subsequent neuronal cell death and memory loss. Cerulenin disrupted the assembly of the TonEBP/NF-κB/AP-1/p300 complex and suppressed the LPS-induced microglial activation and the neuronal damages in animals.
Conclusions:
TonEBP is a key mediator of microglial activation and neuroinflammation relevant to neuronal damage. Cerulenin is an effective blocker of the TonEBP actions.
Insights
Transcription factor TonEBP mediates microglial activation and neuroinflammation. Blocking TonEBP with cerulenin reduces LPS-induced microglial activation and neuronal damage, offering therapeutic potential for neurodegenerative diseases.
Area of Science:
- Neuroscience
- Immunology
- Molecular Biology
Background:
- Microglia, the brain's immune cells, are implicated in neurodegenerative diseases.
- TonEBP acts as a transcriptional cofactor for NF-κB in macrophages, promoting pro-inflammatory gene expression.
- The specific role of microglial TonEBP in neuroinflammation was investigated.
Purpose of the Study:
- To elucidate the function of TonEBP in microglia.
- To determine TonEBP's role in lipopolysaccharide (LPS)-induced neuroinflammation.
- To evaluate cerulenin as a potential therapeutic agent targeting TonEBP.
Main Methods:
- Utilized BV2 microglial cell line and lentiviral shRNA for TonEBP knockdown.
- Generated myeloid-specific TonEBP knockout mice.
- Employed cerulenin to inhibit TonEBP's cofactor activity.
Main Results:
- TonEBP deficiency suppressed LPS-induced pro-inflammatory cytokine and enzyme expression in BV2 cells.
- TonEBP was identified as a cofactor for both NF-κB and AP-1 transcription factors.
- Myeloid-specific TonEBP deletion prevented LPS-induced microglia activation, neuronal death, and memory deficits.
- Cerulenin disrupted the TonEBP/NF-κB/AP-1/p300 complex, mitigating microglial activation and neuronal damage in vivo.
Conclusions:
- TonEBP is a critical mediator of microglial activation and neuroinflammation.
- Targeting TonEBP with cerulenin effectively inhibits neuroinflammatory processes and associated neuronal damage.
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