Abstract
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.
Highlights
Accumulated studies have revealed that general anesthetics could induce neurotoxicity, followed by long-lasting memory and learning abnormalities
To identify genes related to microglia activation, we performed RNA sequencing analysis in BV2 cells with or without LPS stimulation
By merging upregulated Differentially expressed genes (DEGs) from three independent studies (GSE18740, GSE22639, and GSE70689), we noticed that 28 genes (Cd69, Ikbke, Tlr2, Nfkbia, Rab20, Nos2, Cxcl2, Ptgs2, Il1a, Icam1, Tgm2, Casp4, Nfkbie, Tnf, Gpr84, Relb, Plk2, Saa3, Il6, Il1b, Traf1, Ccrl2, Tnfaip3, Stx11, Nfkbiz, Cxcl10, Slc11a2, and Slfn2) were commonly upregulated in activated microglia (Figure 1(b))
Summary
Accumulated studies have revealed that general anesthetics could induce neurotoxicity, followed by long-lasting memory and learning abnormalities. Microglia can secrete various inflammatory cytokines, chemokines, and growth factors and undergo significant morphological changes in response to CNS injuries [7,8,9]. Propofol has been reported to exert several anti-inflammatory effects on microglia. Knowledge regarding the molecular mechanism underlying the anti-inflammatory properties of propofol in microglia activation is still limited. Emerging studies reveal a neuroprotective effect of propofol in diverse diseases of neuronal injuries via modulating microglia activation. BV2 cells and primary microglia were used for functional verification and mechanism studies. 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. 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
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