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Published on: August 15, 2012
Propofol Suppresses Microglia Inflammation by Targeting TGM2/NF-κB Signaling
Yuanyuan Hou1,2, Xi Xiao1,2, Wei Yu1
1Department of Anesthesiology, The Fourth Affiliated Hospital of the Harbin Medical University, Harbin, 150001 Heilongjiang Province, China.
Background:
Propofol is a known intravenous hypnotic drug used for induction and maintenance of sedation and general anesthesia. Emerging studies also reveal a neuroprotective effect of propofol in diverse diseases of neuronal injuries via modulating microglia activation. In this study, we aimed to uncover the downstream targets of propofol in this process.
Methods:
RNA sequencing analysis to identify genes implicated in the propofol-mediated neuroprotective effect. Quantitative real-time PCR, enzyme-linked immunosorbent assay, and Western blotting analysis were performed to analyze inflammatory gene expression, cytokine levels, and TGM2. BV2 cells and primary microglia were used for functional verification and mechanism studies.
Results:
The multifunctional enzyme transglutaminase 2 (TGM2) was identified as a putative functional mediator of propofol. TGM2 was significantly upregulated in lipopolysaccharide- (LPS-) primed BV2 cells. Genetic silencing of TGM2 abolished LPS-induced microglial activation. Notably, gain-of-function experiments showed that the proinflammatory effects of TGM2 were dependent on its GTP binding activity instead of transamidase activity. Then, TGM2 was revealed to activate the NF-κB signaling pathway to facilitate microglial activation. Propofol can inhibit TGM2 expression and NF-κB signaling in BV2 cells and primary microglia. Ectopic expression of TGM2 or constitutively active IKKβ (CA-IKKβ) can compromise propofol-induced anti-inflammatory effects.
Conclusions:
Our findings suggest that TGM2-mediated activation of NF-κB signaling is an important mechanism in the propofol-induced neuroprotective effect that prevents microglial activation.
Insights
Propofol
Area of Science:
- Neuroscience
- Pharmacology
- Immunology
Background:
- Propofol is an anesthetic with emerging neuroprotective properties.
- It modulates microglia activation, a key factor in neuronal injury.
- Understanding propofol's downstream targets is crucial for its therapeutic potential.
Purpose of the Study:
- To identify downstream targets of propofol's neuroprotective effects.
- To elucidate the mechanism by which propofol modulates microglia activation.
Main Methods:
- RNA sequencing to identify key genes.
- Quantitative real-time PCR, ELISA, and Western blotting for validation.
- Cellular studies using BV2 and primary microglia for functional analysis.
Main Results:
- Transglutaminase 2 (TGM2) was identified as a mediator.
- TGM2 upregulation promoted microglial activation via NF-κB signaling.
- Propofol inhibited TGM2 expression and NF-κB activation.
Conclusions:
- TGM2-mediated NF-κB activation is a key mechanism in propofol's neuroprotection.
- Propofol prevents microglial activation by inhibiting this pathway.
- This highlights TGM2 as a potential therapeutic target.
