Zhang Wencui, Jiao Bo, Yu Shangchen, Zhang Kaiwen, Sun Jiaoli, Liu Baowen, Zhang Xianwei
Department of Anesthesiology and Pain Medicine, Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, and Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, China.
Department of Anesthesiology and Pain Medicine, Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, and Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, China.
Free Radic Biol Med. 2025 Feb 1;227:143-156. doi: 10.1016/j.freeradbiomed.2024.12.004. Epub 2024 Dec 4.
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.
小胶质细胞介导的神经炎症在神经性疼痛的进展中起着关键作用。小胶质细胞中烟酰胺腺嘌呤二核苷酸磷酸氧化酶（NOX）产生的活性氧（ROS）诱导的氧化损伤驱动促炎性小胶质细胞活化。最近的证据表明，中枢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，而ACE2/血管紧张素（1-7）/Mas受体（MasR）轴则起到抵消作用。虽然针对脊髓AT1R的干预已被证明可减轻伤害性超敏反应，但其机制仍不清楚。在这里，我们发现，大鼠 spared 神经损伤（SNI）诱导的机械性异常性疼痛与脊髓中M1样小胶质细胞活化、氧化应激以及ACE/Ang II/AT1R轴的过度激活有关。SNI后，在活化的背角小胶质细胞中观察到AT1R和NOX2表达增加。用氯沙坦钾（LOP）阻断AT1R可抑制NOX2介导的氧化应激，并促进LPS处理的BV-2细胞中小胶质细胞从促炎性M1表型向抗炎性M2表型转变。此外，NOX2过表达触发了高迁移率族蛋白B1/核因子-κB（HMGB1/NF-κB）信号通路的激活。鞘内注射LOP有效抑制了SNI诱导的小胶质细胞中NOX2的过度激活，并抑制了HMGB1/NF-κB通路，减轻了氧化应激，使脊髓中小胶质细胞极化从M1转变为M2，从而减轻神经炎症和疼痛超敏反应。总的来说，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，突出了通过NOX2依赖性机制对小胶质细胞中氧化还原稳态的调节。
