Propofol Ameliorates Microglia Activation by Targeting MicroRNA-221/222-IRF2 Axis

Abstract

Background. Propofol is a widely used intravenous anesthetic drug with potential neuroprotective effect in diverse diseases of neuronal injuries such as traumatic brain injury and ischemic stroke. However, the underlying molecular mechanism remains largely unknown. Methods. Real-time qPCR, enzyme-linked immunosorbent assay, and Western blotting were used to identify the expression pattern of miR-221/222, inflammatory genes, cytokines, and IRF2. The biological roles and mechanisms of propofol in microglia activation were determined in BV2 cells and primary microglia. Bioinformatic analysis and luciferase reporter assay were used to confirm the regulatory role of miR-221/222 in Irf2 expression. Results. We found that miR-221 and miR-222 were downstream targets of propofol and were consistently upregulated in lipopolysaccharide- (LPS-) primed BV2 cells. Gain- and loss-of-function studies revealed that miR-221 and miR-222 were profoundly implicated in microglia activation. Then, interferon regulatory factor 2 (Irf2) was identified as a direct target gene of miR-221/222. IRF2 protein levels were reduced by miR-221/222 and increased by propofol treatment. Ectopic expression of IRF2 attenuated the proinflammatory roles induced by LPS in BV2 cells. More importantly, the suppressive effects of propofol on LPS-primed activation of BV2 cells or primary mouse microglia involved the inhibition of miR-221/222-IRF2 axis. Conclusions. Our study highlights the critical function of miR-221/222, which inhibited Irf2 translation, in the anti-inflammatory effects of propofol, and provides a new perspective for the molecular mechanism of propofol-mediated neuroprotective effect.

The ENCODE mouse postnatal developmental time course identifies regulatory programs of cell types and cell states

“…3c), none of which have been implicated in regional microglial signatures. Genes involved in microglia polarization (e.g., Irf8 62 and Stat3 63 ), activation and inflammatory response (e.g., Spi1 64 and Irf2 65 ), and establishment of microglia identity and immune response (e.g. Sall1 66 , Sall3 67 , Etv5 68 , and Zeb1 69 all have high mean average (A) values in both cortex and hippocampus microglia topics.…”

Propofol inhibits neuroinflammation and metabolic reprogramming in microglia in vitro and in vivo

“…A number of mechanisms have been proposed to account for propofol anti-inflammatory effect in microglia, including downregulation of TLR4 expression ( Qin et al, 2013 ), inactivation of GSK-3β ( Gui et al, 2012 ), inhibition of NMDA receptor and NADPH oxidases ( Luo et al, 2013 ) as well as suppression of miR-155 and miR-221/222 ( Zheng et al, 2017 ; Xiao et al, 2021 ). Recent study reported that propofol regulated the activity of HIF-1α to reduce prostate cancer cells malignancy ( Huang et al, 2014 ).…”

Effect of General Anesthetic Agents on Microglia

“…Meanwhile, the anti-inflammatory transcription factor Irf2 has been identified as a direct target gene of miR-221/222, binding its 3'-untranslated region to inhibit its translation [ 74 ]. Propofol can inhibit microglial activation through the miR-221/222-Irf2 axis [ 75 ]. MiR-221 and miR-222 are involved in regulating physiological vascular processes in healthy organisms, yet they also promote a malignant phenotype by mediating the proliferation, differentiation, and invasive capacity of cancer cells [ 76 ].…”