SIRT1 Promotes M2 Microglia Polarization via Reducing ROS-Mediated NLRP3 Inflammasome Signaling After Subarachnoid Hemorrhage.
SIRT1 Promotes M2 Microglia Polarization via Reducing ROS-Mediated NLRP3 Inflammasome Signaling After Subarachnoid Hemorrhage.
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SIRT1 通过减少蛛网膜下腔出血后 ROS 介导的 NLRP3 炎性体信号转导促进 M2 小胶质细胞极化
DOI：
10.3389/fimmu.2021.770744
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发表时间：
2021
影响因子：
7.3
通讯作者：
Zhang XS
中科院分区：
文献类型：
--
作者：
Xia DY;Yuan JL;Jiang XC;Qi M;Lai NS;Wu LY;Zhang XS
越来越多的证据表明，调节小胶质细胞从促炎M1表型到抗炎M2状态的极化可能是治疗蛛网膜下腔出血（SAH）损伤的潜在治疗方法。我们的前期研究表明，sirtuin 1（SIRT 1）可以通过减轻氧化损伤和神经炎症来改善SAH早期脑损伤（EBI）。然而，SIRT 1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，EX 527，一种有效的选择性SIRT 1抑制剂，增强SAH后小胶质细胞M1极化和小胶质细胞中含pyrin结构域3（NLRP 3）炎性小体的激活。给予SIRT 1激动剂SRT 1720显著增强SIRT 1表达，改善功能恢复，并改善SAH后的脑水肿和神经元死亡。此外，SRT 1720调节小胶质细胞极化从M1表型向M2表型偏移。此外，SRT 1720显著降低叉头盒蛋白O 1的乙酰化，抑制活性氧（ROS）的过度产生，并抑制NLRP 3炎性体信号传导。相比之下，EX 527减弱SIRT 1的上调并逆转SRT 1720对ROS-NLRP 3炎性小体活化和EBI的抑制作用。类似地，在体外，SRT 1720抑制炎症反应、氧化损伤和神经元变性，并提高神经元和小胶质细胞共培养系统中的细胞活力。这些作用与ROS-NLRP 3炎性体的抑制和SIRT 1信号传导的刺激相关，这可以被EX 527减弱。总之，这些发现表明，SRT 1720，一种SIRT 1激动剂，可以通过调节ROS介导的NLRP 3炎性体信号传导将小胶质细胞表型向M2转移来改善SAH后的EBI。
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, in vitro, 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 via modulation of ROS-mediated NLRP3 inflammasome signaling.
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影响因子：
16.2
作者：
Herskovits AZ;Guarente L
通讯作者：
Guarente L
影响因子：
--
作者：
Beckhauser TF;Francis-Oliveira J;De Pasquale R
通讯作者：
De Pasquale R
DOI：
10.1016/j.bbi.2016.12.012
发表时间：
2017-03
期刊：
Brain, behavior, and immunity
影响因子：
--
作者：
Lan X;Han X;Li Q;Li Q;Gao Y;Cheng T;Wan J;Zhu W;Wang J
通讯作者：
Wang J
影响因子：
3.7
作者：
Kooijman E;Nijboer CH;van Velthoven CT;Mol W;Dijkhuizen RM;Kesecioglu J;Heijnen CJ
通讯作者：
Heijnen CJ
影响因子：
5.6
作者：
Hu, Li;Zhang, Shutian;Xia, Chunmei
通讯作者：
Xia, Chunmei