MiR-142a-3p and miR-155-5p reduce methamphetamine-induced inflammation: Role of the target protein Peli1


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Abstract

Methamphetamine (METH) is a highly addictive stimulant and METH exposure can induce a series of neuroinflammatory effects. Peli1 is a novel and important E3 ubiquitin-protein ligase contributing to neuroinflammation; targeting Peli1 may thus provide promising therapeutic strategies for neuroinflammation. In addition to the classic MyD88-dependent or MyD88-independent pathways, miRNAs may also be involved in Peli1 modulation. In the present study, two novel miRNAs, miR-142a-3p and miR-155-5p, that were predicted to target Peli1 using bioinformatics were chosen, and their unique roles in METH-induced neuroinflammation via regulating Peli1 expression were identified. Our results showed that miR-142a-3p was significantly reduced in METH-induced neuroinflammation and was negatively associated with Peli1 expression both in BV2 cells and in the brain of mouse. MiR-155-5p was significantly reduced by METH in vitro but increased in vivo. A luciferase reporter assay was performed to reveal that miR-142a-3p and miR-155-5p bound specifically to Peli1, an effect that was completely abolished by the Peli1 binding site mutation. Reciprocally, the overexpression of miR-142a-3p and miR-155-5p could directly suppress Peli1 expression and could protect against the inflammatory effects of METH treatment partially through activating p38 MAPK and NF-κB inflammatory pathways. In conclusion, the present study reveals a novel signaling pathway, the miR-142a-3p/miR-155-5p/Peli1 axis in METH-mediated neuroinflammation, and this pathway could be a potential therapeutic target for METH-mediated neurotoxicity.HighlightsPeli1, miR-142a-3p and miR-155-5p participated in METH-induced neuroinflammation.MiR-142a-3p and miR-155-5p directly bound to the 3′-UTR of Peli1.MiR-142a-3p and miR-155-5p mimics suppressed p38 MAPK and NF-κB pathways.MiR-142a-3p and miR-155-5p mimics attenuated METH-induced neuroinflammation.

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