• Neuroscience · Oct 2024

    METTL3 inhibits microglial pyroptosis in neonatal hypoxia-ischemia encephalopathy by regulating GPR39 expression in an m6A-HuR-dependent manner.

    • Xili Jiang, Wei Zhang, and Shucai Xie.
    • Department of Radiology, The Second People's Hospital of Hunan Province/Brain Hospital of Hunan Province, Changsha 410008, China.
    • Neuroscience. 2024 Oct 24; 563: 175187175-187.

    BackgroundNeonatal hypoxia-ischemia encephalopathy (HIE) is a significant reason for neonatal mortality and prolonged disability. We have previously revealed that GPR39 activation attenuates neuroinflammation in a neonatal HIE rat model. This study aimed to investigate whether GPR39 affected microglial pyroptosis post-HIE.MethodsA neonatal rat model of HIE and a microglia cell model of oxygen-glucose deprivation (OGD) were established. Neuronal loss and cerebral infarction were assessed by using TTC, H&E staining, and Nissl staining. Pyroptosis was evaluated with western blot, LDH assay kit, ELISA, and flow cytometry. Total m6A level and GPR39 m6A modification were determined using m6A dot blot and MeRIP. The interaction between METTL3/HuR/GSK3β and GPR39 was analyzed by performing molecular interaction experiments. GPR39 mRNA stability was examined with actinomycin D.ResultsThe level of GPR39 was increased in neonatal HIE rats and OGD-treated microglia. Brain injury and neuronal loss were significantly increased in the HIE model when GPR39 was knocked down. GPR39 knockdown aggravated NLRP3 inflammasome-mediated microglial pyroptosis. METTL3 upregulated GPR39 expression in an m6A-dependent manner. METTL3 enhanced the interaction of HuR and GPR39. In OGD-exposed microglia, METTL3 elevated GPR39 expression and mRNA stability, which declined after HuR depletion. METTL3 knockdown promoted microglial pyroptosis, which was reversed by GPR39 agonist. Furthermore, microglial pyroptosis was inhibited by GPR39 upregulation, but the outcome was reverted by GSK3β activator SNP.ConclusionMETTL3 inhibits microglial pyroptosis in neonatal HIE via regulating m6A-HuR dependent stabilization of GPR39, which contributes to therapeutics development for neonatal HIE.Copyright © 2024. Published by Elsevier Inc.

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