Propofol Suppresses Microglia Inflammation by Targeting TGM2/NF-κB Signaling

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.

In Vitro Effect of Propofol on the Expression of Genes Involved in Inflammation and Apoptosis in Corneal Activated Keratocytes

“…Moreover, propofol treatment could downregulate IL-6 expression in the concentration of 5 mM. This finding was in consistence with the report of Hou et al 31 who reported the inhibitory effect of propofol on IL-1b and IL-6 at the mRNA and protein level. IL-1 (a and b) is one of the primary regulators and known proinflammatory cytokines that plays an essential role in the corneal inflammatory response, wound healing, and immune modulation.…”

Construction of a predictive model for immunotherapy efficacy in lung squamous cell carcinoma based on the degree of tumor-infiltrating immune cells and molecular typing

“…PI3K/AKT/ mammalian target of rapamycin (mTOR) signaling pathway could be regulated by ALOX5 [80], SCARF1 [81] and TGM2 [82]. There are seven genes involved in the regulation of nuclear transcription factor-κB (NF-κB) signaling pathway, such as ALOX5 [83], MARCO [84], NANOG [85], NLRP12 [74], NTSR1 [75], TGM2 [86], and VSTM1 [87]. Toll-like receptors (TLRs) signaling pathway could be regulated by FCGR2A [88], MARCO [89], NANOG [90], NLRP12 [74], and PF4 [91].…”

Dual roles of anesthetics in postoperative cognitive dysfunction: Regulation of microglial activation through inflammatory signaling pathways

“…Accumulating evidence has confirmed that propofol targets NF-kB and its upstream signaling pathways to inhibit microglial activation in vivo and in vitro (80,(108)(109)(110). Microglial activation in the spinal cord induced by peripheral inflammation can be reversed by propofol via inhibition of the MAPK ERK1/2/NF-kB pathway (80).…”

“…Microglial activation in the spinal cord induced by peripheral inflammation can be reversed by propofol via inhibition of the MAPK ERK1/2/NF-kB pathway (80). In the LPS-induced cell model, the release of pro-inflammatory cytokines and the genes TICAM1, IRF3, and NFKB1 involved in NF-kB pathway are downregulated by propofol (108,109). TLR4 and its adaptor protein MyD88, key upstream inflammatory mediators that activate NF-kB, are also downregulated by propofol, thus inhibiting the microglial activation induced by LPS (110,111).…”