Department of Neurosurgery, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, China.
Department of Neurosurgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China.
Front Immunol. 2021 Nov 24;12:770744. doi: 10.3389/fimmu.2021.770744. eCollection 2021.
Mounting evidence has suggested that modulating microglia polarization from pro-inflammatory M1 phenotype to anti-inflammatory M2 state might be a potential therapeutic approach in the treatment of subarachnoid hemorrhage (SAH) injury. Our previous study has indicated that sirtuin 1 (SIRT1) could ameliorate early brain injury (EBI) in SAH by reducing oxidative damage and neuroinflammation. However, the effects of SIRT1 on microglial polarization and the underlying molecular mechanisms after SAH have not been fully illustrated. In the present study, we first observed that EX527, a potent selective SIRT1 inhibitor, enhanced microglial M1 polarization and nod-like receptor pyrin domain-containing 3 (NLRP3) inflammasome activation in microglia after SAH. Administration of SRT1720, an agonist of SIRT1, significantly enhanced SIRT1 expression, improved functional recovery, and ameliorated brain edema and neuronal death after SAH. Moreover, SRT1720 modulated the microglia polarization shift from the M1 phenotype and skewed toward the M2 phenotype. Additionally, SRT1720 significantly decreased acetylation of forkhead box protein O1, inhibited the overproduction of reactive oxygen species (ROS) and suppressed NLRP3 inflammasome signaling. In contrast, EX527 abated the upregulation of SIRT1 and reversed the inhibitory effects of SRT1720 on ROS-NLRP3 inflammasome activation and EBI. Similarly, , SRT1720 suppressed inflammatory response, oxidative damage, and neuronal degeneration, and improved cell viability in neurons and microglia co-culture system. These effects were associated with the suppression of ROS-NLRP3 inflammasome and stimulation of SIRT1 signaling, which could be abated by EX527. Altogether, these findings indicate that SRT1720, an SIRT1 agonist, can ameliorate EBI after SAH by shifting the microglial phenotype toward M2 modulation of ROS-mediated NLRP3 inflammasome signaling.
越来越多的证据表明，将小胶质细胞从促炎 M1 表型向抗炎 M2 状态极化调节可能是蛛网膜下腔出血 (SAH) 损伤治疗的一种潜在治疗方法。我们之前的研究表明，沉默信息调节因子 1 (SIRT1) 通过减少氧化损伤和神经炎症可以改善 SAH 后的早期脑损伤 (EBI)。然而，SIRT1 对 SAH 后小胶质细胞极化的影响及其潜在的分子机制尚未完全阐明。在本研究中，我们首先观察到，强效选择性 SIRT1 抑制剂 EX527 增强了 SAH 后小胶质细胞中 M1 极化和核苷酸结合寡聚结构域样受体含pyrin 结构域蛋白 3 (NLRP3) 炎性小体的激活。SIRT1 的激动剂 SRT1720 的给药显著增强了 SIRT1 的表达，改善了功能恢复，并减轻了 SAH 后的脑水肿和神经元死亡。此外，SRT1720 调节了小胶质细胞从 M1 表型向 M2 表型的极化转变。此外，SRT1720 显著降低了叉头框蛋白 O1 的乙酰化，抑制了活性氧 (ROS) 的过度产生，并抑制了 NLRP3 炎性小体信号。相反，EX527 减弱了 SIRT1 的上调，并逆转了 SRT1720 对 ROS-NLRP3 炎性小体激活和 EBI 的抑制作用。同样，SRT1720 在神经元和小胶质细胞共培养系统中抑制炎症反应、氧化损伤和神经元变性，提高神经元和小胶质细胞的活力。这些作用与 ROS-NLRP3 炎性小体的抑制和 SIRT1 信号的刺激有关，而 EX527 可以减弱这种作用。总之，这些发现表明，SIRT1 激动剂 SRT1720 通过调节 ROS 介导的 NLRP3 炎性小体信号，将小胶质细胞表型向 M2 极化转变，从而改善 SAH 后的 EBI。
