Propofol Inhibits Microglial Activation via miR-106b/Pi3k/Akt Axis

Abstract

Propofol is an established intravenous anesthetic agent with potential neuroprotective effects. In this study, we investigated the roles and the underlying mechanisms of propofol in inhibiting the pro-inflammatory responses of microglia. Propofol significantly reduced the messenger RNA (mRNA) levels of Tnf, Nos2, and NF-κB pathway related genes Ticam1, Myd88, Irf3, and Nfkb1 in lipopolysaccharide (LPS)-treated primary microglia. After screening the miRNA profiles in microglia under LPS and propofol treatment conditions, we found propofol abrogated the LPS-induced misexpression of miRNAs including miR-106b, miR-124, miR-185, and miR-9. Perturbation of function approaches suggested miR-106b as the core miRNA that mediated the anti-inflammatory effects of propofol on microglial activation. RNA sequencing (RNA-seq) analysis further identified Pi3k/Akt signaling as one of the most affected pathways after miR-106b perturbation of function. The treatment of Pi3k/Akt signaling agonist 740Y-P elevated miR-106b-reduced Akt phosphorylation and abolished the inhibitory effects of miR-106b on the pro-inflammatory responses of microglia. Our results suggest propofol inhibits microglial activation via miR-106b/Pi3k/Akt axis, shedding light on a novel molecular mechanism of propofol-mediated immunomodulatory effects and implying propofol as potential therapeutics for treating neuroinflammation-related neurodegenerative diseases.

Recent progress on the role of non-coding RNA in postoperative cognitive dysfunction

“…In a recent in vitro model, miR-124 overexpression with a concomitant decrease of its target (VAMP3) expression led to a decrease of inflammatory factors associated with microglial activation post-surgery ( Chen et al, 2019b ). Other microRNA types and their targets, including miR-155/SOCS1 ( Zheng et al, 2018 ), and miR-106b/Dusp9 ( Liu et al, 2021 ), were suggested to regulate microglial function in LPS-activated microglia treated by anesthetic agents.…”

Bioinformatics analysis and in vivo validation of ferroptosis-related genes in ischemic stroke

“…However, the top-ranking predicted miRNAs were hsa-miR-106a-5p and hsa-miR-106b-5p. miR-106 is associated with microglial activation and neuroinflammatory diseases ( Liu et al, 2021 ). Given the complexity of its regulatory network, miR-106 may represent an essential target for the regulation of stroke.…”

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).…”

“…The PI3k/Akt pathway is also involved in the anti-inflammatory mechanisms of propofol on microglial activation (109,123). Liu et al (109) found that miRNA miR-106b acted as an upstream antiinflammatory regulator, inhibiting Akt phosphorylation; propofol induced the overexpression of miR-106b to attenuate LPS-induced microglial activation by inhibiting the PI3k/Akt pathway (109).…”