Microglial TonEBP mediates LPS-induced inflammation and memory loss as transcriptional cofactor for NF-?B and AP-1.

ABSTRACT: 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-?B 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-?B 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-?B 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-?B. 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-?B/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.

SUBMITTER: Jeong GW 

PROVIDER: S-EPMC7722447 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature