Mechanism of Mettl14 regulating AIM2 inflammasome activation and neuronal apoptosis and pyroptosis in spinal cord injury by mediating PPARγ m6A methylation.

IF 3.7 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Journal of physiology and biochemistry Pub Date : 2024-10-14 DOI:10.1007/s13105-024-01047-6
Fan Wu, Liqun Li, Zhigang Li, Dabiao Zhou, Zhihui Huang, Dawei Sang, Chizi Hao
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引用次数: 0

Abstract

Spinal cord injury (SCI) represents a destructive pathological and neurological state. Methyltransferase-like 14 (Mettl14)-mediated m6A modification links to spinal cord injury (SCI), and we explored its mechanism. SCI mouse models were subjected to si-Mettl14 and si-negative control treatments and mouse behavior, pathological condition and apoptosis assessments. The oxygen/glucose deprivation (OGD)-induced spinal cord neuronal cell models were processed with si-Mettl14 and si-peroxisome proliferator-activated receptor γ (PPARγ) plasmids, and pcDNA3.1-YTHDF2 or synthetic dsDNA Poly(dA: dT), followed by viability and apoptosis evaluation by MTT and flow cytometry. Levels of Mettl14, PPARγ, and YTHDF2 mRNAs and proteins, AIM2 inflammasome activation-associated and pyroptosis marker proteins, PPARγ m6A methylation and pyroptosis-related inflammatory factors were determined by RT-qPCR, Western blot, Me-RIP and ELISA, with PPARγ mRNA stability and YTHDF2-PPARγ interaction assessed. Mettl14 and PPARγ m6A modification levels rose in SCI spinal cord tissues, while PPARγ levels dropped. Mettl14 knockdown dampened m6A modification, up-regulated PPARγ levels, weakened neuronal apoptosis, and ameliorated SCI in mice. OGD down-regulated PPARγ and accelerated OGD-induced neuronal apoptosis and pyroptosis via inducing Mettl14-mediated m6A modification. Mettl14 amplified PPARγ mRNA degradation and down-regulated PPARγ by mediating m6A methylation via the YTHDF2-dependent pathway. Mettl14 silencing-mediated PPARγ m6A methylation mitigated OGD-induced neuronal apoptosis and pyroptosis by inactivating AIM2 inflammasome. Mettl14 triggered activated AIM2 inflammasomes, promoted neuronal apoptosis and pyroptosis, and worsened SCI in SCI mice via mediating PPARγ m6A methylation. Mettl14 regulates AIM2 inflammasome activation, and redounds to spinal cord neuronal apoptosis and pyroptosis in SCI by mediating m6A methylation of PPARγ.

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Mettl14 通过介导 PPARγ m6A 甲基化调节脊髓损伤中 AIM2 炎症小体激活、神经元凋亡和热凋亡的机制
脊髓损伤(SCI)是一种破坏性病理和神经状态。甲基转移酶样14(Mettl14)介导的m6A修饰与脊髓损伤(SCI)有关,我们对其机制进行了探索。我们对SCI小鼠模型进行了si-Mettl14和si-阴性对照处理,并对小鼠的行为、病理状态和细胞凋亡进行了评估。用si-Mettl14和si-过氧化物酶体增殖激活受体γ(PPARγ)质粒、pcDNA3.1-YTHDF2或合成dsDNA Poly(dsA:dsT)处理氧/葡萄糖剥夺(OGD)诱导的脊髓神经元细胞模型,然后用MTT和流式细胞术评估细胞活力和凋亡。通过 RT-qPCR、Western 印迹、Me-RIP 和 ELISA 测定了 Mettl14、PPARγ 和 YTHDF2 mRNA 和蛋白质、AIM2 炎性体活化相关蛋白和炎性体标志蛋白、PPARγ m6A 甲基化和炎性体相关炎性因子的水平,并评估了 PPARγ mRNA 的稳定性和 YTHDF2-PPARγ 的相互作用。在SCI脊髓组织中,Mettl14和PPARγ m6A修饰水平上升,而PPARγ水平下降。Mettl14敲除抑制了m6A修饰,上调了PPARγ水平,削弱了神经元凋亡,并改善了小鼠的SCI。OGD 通过诱导 Mettl14 介导的 m6A 修饰,下调 PPARγ 并加速 OGD 诱导的神经元凋亡和热凋亡。Mettl14 通过 YTHDF2 依赖性途径介导 m6A 甲基化,扩大 PPARγ mRNA 降解并下调 PPARγ。Mettl14沉默介导的PPARγ m6A甲基化通过使AIM2炎性体失活,减轻了OGD诱导的神经元凋亡和脓毒症。Mettl14通过介导PPARγ m6A甲基化,触发活化的AIM2炎性体,促进神经元凋亡和裂解,并恶化SCI小鼠的SCI。Mettl14通过介导PPARγ的m6A甲基化,调节AIM2炎性体的激活,并导致SCI小鼠脊髓神经元凋亡和脓毒症。
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来源期刊
Journal of physiology and biochemistry
Journal of physiology and biochemistry 生物-生化与分子生物学
CiteScore
6.60
自引率
0.00%
发文量
86
审稿时长
6-12 weeks
期刊介绍: The Journal of Physiology and Biochemistry publishes original research articles and reviews describing relevant new observations on molecular, biochemical and cellular mechanisms involved in human physiology. All areas of the physiology are covered. Special emphasis is placed on the integration of those levels in the whole-organism. The Journal of Physiology and Biochemistry also welcomes articles on molecular nutrition and metabolism studies, and works related to the genomic or proteomic bases of the physiological functions. Descriptive manuscripts about physiological/biochemical processes or clinical manuscripts will not be considered. The journal will not accept manuscripts testing effects of animal or plant extracts.
期刊最新文献
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