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

Affiliation

Key Laboratory of Modern Toxicology (NJMU), Ministry of Education, Department of Toxicology, School of Public Health, Nanjing Medical University, 818 Tianyuan East Road, Nanjing, Jiangsu 211166, China. Electronic address: [Email]

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.

Keywords

Methamphetamine,Neuroinflammation,Peli1,miR-142a-3p,miR-155-5p,

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