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.
Highlights
Neurodegenerative diseases like Alzheimer’s disease and Parkinson’s disease are characterized by neuronal loss and chronic neuroinflammation (Amor and Woodroofe, 2014; Nichols et al, 2019)
We demonstrated the inhibitory effects of propofol on the activation of primary microglia, which confirmed the results obtained from BV2 cells
We further demonstrated that miR-106 is the core miRNA that mediated the protective effects of propofol against the inflammatory responses in microglial cells
Summary
Neurodegenerative diseases like Alzheimer’s disease and Parkinson’s disease are characterized by neuronal loss and chronic neuroinflammation (Amor and Woodroofe, 2014; Nichols et al, 2019). Microglia, being the resident immune cells in the central nervous system (CNS), are the central mediators of neuroinflammation to control host defense and tissue degeneration/regeneration. Propofol Inhibits Microglial Activation (Wolf et al, 2017). Microglia change into a pro-inflammatory phenotype with the activation of the nuclear factor-kappa B (NF-κB)related signaling pathways and the excessive expression of pro-inflammatory factors such as tumor necrosis factor α (TNF-α) and inducible nitric oxide synthase (iNOS), leading to neuroinflammation (Michels et al, 2015; Thawkar and Kaur, 2019). Our group, together with other labs, have reported that propofol is able to modulate the phenotype of BV2 microglial cells and assert anti-inflammatory effects (Luo et al, 2018; Wu Q. et al, 2018; Zheng et al, 2018; Liu et al, 2019). The molecular mechanisms of propofol-mediated microglial phenotype transition remain to be elucidated
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