脊髓AT1R通过小胶质细胞中nox2依赖的氧化还原信号参与神经炎症和神经性疼痛。

IF 7.1 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Wencui Zhang, Bo Jiao, Shangchen Yu, Kaiwen Zhang, Jiaoli Sun, Baowen Liu, Xianwei Zhang
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引用次数: 0

摘要

小胶质细胞介导的神经炎症在神经性疼痛的进展中起关键作用。由NADPH氧化酶(NOX)产生的活性氧(ROS)诱导的小胶质细胞氧化损伤驱动促炎性小胶质细胞活化。最近的证据表明,中央肾素血管紧张素系统(RAS)参与氧化应激和神经炎症,血管紧张素转换酶/血管紧张素II/血管紧张素受体-1 (ACE/Ang II/AT1R)轴通过增加ROS产生促进炎症,被ACE2/Ang (1-7)/ Mas受体(MasR)轴抵消。虽然针对脊髓AT1R的干预措施已被证明可以减轻伤害性超敏反应;然而,其机制仍然难以捉摸。本研究发现,SNI诱导的大鼠机械异常性痛与m1样小胶质细胞激活、氧化应激和脊髓ACE/Ang II/AT1R轴过度活性相关。SNI处理后,活化的背角小胶质细胞中AT1R和NOX2表达增加。losartan钾(LOP)阻断AT1R可抑制nox2介导的氧化应激,并促进lps处理的BV-2细胞小胶质细胞从促炎M1表型向抗炎M2表型转变。此外,NOX2过表达触发高迁移率组盒1/核因子κB (HMGB1/NF-κB)信号通路的激活。鞘内给予LOP可有效抑制sni诱导的小胶质细胞NOX2过激活,抑制HMGB1/NF-kB通路,降低氧化应激,使脊髓小胶质细胞的极化由M1向M2转变,从而减轻神经炎症和疼痛超敏反应。总之,这些发现强调了脊髓AT1R在神经性疼痛中的神经免疫调节作用,强调了通过NOX2依赖机制对小胶质细胞氧化还原稳态的调节。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Spinal AT1R contributes to neuroinflammation and neuropathic pain via NOX2-dependent redox signaling in microglia

Spinal AT1R contributes to neuroinflammation and neuropathic pain via NOX2-dependent redox signaling in microglia
Microglia-mediated neuroinflammation demonstrates a crucial act in the progression of neuropathic pain. Oxidative damage induced by reactive oxygen species (ROS) derived from NADPH oxidase (NOX) in microglia drives proinflammatory microglia activation. Recent evidence points to the central renin angiotensin system (RAS) is involved in oxidative stress and neuroinflammation, with the angiotensin converting enzyme/angiotensin II/angiotensin receptor-1 (ACE/Ang II/AT1R) axis promoting inflammation through increased ROS production, counteracted by the ACE2/Ang (1–7)/Mas receptor (MasR) axis. While interventions targeting spinal AT1R have been shown to alleviate nociceptive hypersensitivity; yet the mechanisms remain elusive. Here, we discovered that spared nerve injury (SNI)-induced mechanical allodynia in rats were associated with M1-like microglia activation, oxidative stress and overactivity of ACE/Ang II/AT1R axis in the spinal cord. Increased AT1R and NOX2 expression were observed in activated dorsal horn microglia following SNI. Blockade of AT1R with losartan potassium (LOP) suppressed NOX2-mediated oxidative stress, and promoted a shift in microglia from the proinflammatory M1 phenotype to the anti-inflammatory M2 phenotype in LPS-treated BV-2 cells. Additionally, NOX2 overexpression triggered the activation of the high-mobility group box 1/nuclear factor-kappa B (HMGB1/NF-κB) signaling pathway. Intrathecal administration of LOP effectively inhibited SNI-induced NOX2 overactivation in microglia and suppressed the HMGB1/NF-kB pathway, reducing oxidative stress and shifting the microglia polarization from M1 to M2 in the spinal cord, thereby attenuating neuroinflammation and pain hypersensitivity. Collectively, these findings underscore the neuroimmune-modulating effects of spinal AT1R in neuropathic pain, highlighting the regulation of redox homeostasis in microglia via a NOX2 dependent mechanism.
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来源期刊
Free Radical Biology and Medicine
Free Radical Biology and Medicine 医学-内分泌学与代谢
CiteScore
14.00
自引率
4.10%
发文量
850
审稿时长
22 days
期刊介绍: Free Radical Biology and Medicine is a leading journal in the field of redox biology, which is the study of the role of reactive oxygen species (ROS) and other oxidizing agents in biological systems. The journal serves as a premier forum for publishing innovative and groundbreaking research that explores the redox biology of health and disease, covering a wide range of topics and disciplines. Free Radical Biology and Medicine also commissions Special Issues that highlight recent advances in both basic and clinical research, with a particular emphasis on the mechanisms underlying altered metabolism and redox signaling. These Special Issues aim to provide a focused platform for the latest research in the field, fostering collaboration and knowledge exchange among researchers and clinicians.
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