甲基转移酶 METTL3 通过 SOCS1 的 m6A 甲基化修饰调节神经性疼痛。

IF 4.6 2区 医学 Q1 NEUROSCIENCES
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引用次数: 0

摘要

神经病理性疼痛(NP)的机制被认为是多因素的。细胞因子信号转导抑制因子 1(SOCS1)的变化在神经损伤和炎症中起着至关重要的作用。人们越来越多地观察到表观遗传 RNA 修饰,特别是 N6-甲基腺苷(m6A)甲基化对神经系统的影响。然而,很少有研究调查 m6A 甲基化和 SOCS1 在 NP 分子机制中的联系。本研究探讨了类似 m6A 甲基转移酶 3(METTL3)和 SOCS1 在脊神经结扎(SNL)诱导的雌性 NP 大鼠中的作用和潜在机制。研究发现,在 NP 中,METTL3 和总体 m6A 水平均下调,导致白细胞介素-1β、白细胞介素 6 和肿瘤坏死因子-α 等促炎细胞因子的激活。值得注意的是,SOCS1 mRNA 明显富含 m6A 甲基化修饰,最普遍的 m6A 甲基转移酶 METTL3 通过靶向 151、164 和 966 位的 m6A 甲基化修饰,稳定了 SOCS1 的下调。此外,内源性 SOCS1 的耗竭通过诱导收费样受体 4(TLR4)信号通路促进了 NP 的进展。METTL3 的失调和由此导致的 SOCS1 的 m6A 修饰形成了一个关键的表观遗传调控环,促进了 NP 的进展。以 METTL3/SOCS1 轴为靶点可能会为 NP 的潜在治疗策略提供新的见解。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Methyltransferase METTL3 regulates neuropathic pain through m6A methylation modification of SOCS1
The mechanisms of neuropathic pain (NP) are considered multifactorial. Alterations in the suppressor of cytokine signaling 1 (SOCS1) play a critical role in neural damage and inflammation. Epigenetic RNA modifications, specifically N6-methyladenosine (m6A) methylation, have increasingly been observed to impact the nervous system. Nevertheless, there is a scarcity of studies investigating the connection between m6A methylation and SOCS1 in the molecular mechanisms of NP. This study investigates the roles and potential mechanisms of the m6A methyltransferase like 3 (METTL3) and SOCS1 in female rats with spinal nerve ligation (SNL)-induced NP. It was found that in NP, both METTL3 and overall m6A levels were downregulated, leading to the activation of pro-inflammatory cytokines, such as interleukin-1β, interleukin 6, and tumor necrosis factor-α. Notably, The SOCS1 mRNA is significantly enriched with m6A methylation modifications, with the most prevalent m6A methyltransferase METTL3 stabilizing the downregulation of SOCS1 by targeting m6A methylation modifications at positions 151, 164, and 966.Exogenous supplementation of METTL3 improved NP-related neuroinflammation and behavioral dysfunctions, but these effects could be reversed by the absence of SOCS1. Additionally, the depletion of endogenous SOCS1 promoted NP progression by inducing the toll-like receptor 4 (TLR4) signaling pathway. The dysregulation of METTL3 and the resulting m6A modification of SOCS1 form a crucial epigenetic regulatory loop that promotes the progression of NP. Targeting the METTL3/SOCS1 axis might offer new insights into potential therapeutic strategies for NP.
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来源期刊
Neuropharmacology
Neuropharmacology 医学-神经科学
CiteScore
10.00
自引率
4.30%
发文量
288
审稿时长
45 days
期刊介绍: Neuropharmacology publishes high quality, original research and review articles within the discipline of neuroscience, especially articles with a neuropharmacological component. However, papers within any area of neuroscience will be considered. The journal does not usually accept clinical research, although preclinical neuropharmacological studies in humans may be considered. The journal only considers submissions in which the chemical structures and compositions of experimental agents are readily available in the literature or disclosed by the authors in the submitted manuscript. Only in exceptional circumstances will natural products be considered, and then only if the preparation is well defined by scientific means. Neuropharmacology publishes articles of any length (original research and reviews).
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