Department of Neurosurgery, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
Front Immunol. 2022 Jan 27;13:810582. doi: 10.3389/fimmu.2022.810582. eCollection 2022.
Neuroinflammation has been proven to exert an important effect on brain injury after intracerebral hemorrhage (ICH). Previous studies reported that Didymin possessed anti-inflammatory properties after acute hepatic injury, hyperglycemia-induced endothelial dysfunction, and death. However, the role of Didymin in microglial pyroptosis and neuroinflammation after ICH is unclear. The current study aimed to investigate the effect of Didymin on neuroinflammation mediated by microglial pyroptosis in mouse models of ICH and shed some light on the underlying mechanisms. In this study, we observed that Didymin treatment remarkably improved neurobehavioral performance and decreased BBB disruption and brain water content. Microglial activation and neutrophil infiltration in the peri-hematoma tissue after ICH were strikingly mitigated by Didymin as well. At the molecular level, administration of Didymin significantly unregulated the expression of Rkip and downregulated the expression of pyroptotic molecules and inflammatory cytokines such as Nlrp3 inflammasome, GSDMD, caspase-1, and mature IL-1β, TNF-α, and MPO after ICH. Besides, Didymin treatment decreased the number of Caspase-1-positive microglia and GSDMD-positive microglia after ICH. Inversely, Locostatin, an Rkip-specific inhibitor, significantly abolished the anti-pyroptosis and anti-neuroinflammation effects of Didymin. Moreover, Rkip binding with Asc could interrupt the activation and assembly of the inflammasome. Mechanistically, inhibition of Caspase-1 by VX-765 attenuated brain injury and suppressed microglial pyroptosis and neuroinflammation by downregulation of GSDMD, mature IL-1β, TNF-α, and MPO based on Locostatin-treated ICH. Taken together, Didymin alleviated microglial pyroptosis and neuroinflammation, at least in part through the Asc/Caspase-1/GSDMD pathway upregulating Rkip expression after ICH. Therefore, Didymin may be a potential agent to attenuate neuroinflammation its anti-pyroptosis effect after ICH.
神经炎症已被证明对脑出血 (ICH) 后的脑损伤有重要影响。先前的研究表明，二氢杨梅素在急性肝损伤、高血糖诱导的内皮功能障碍和细胞死亡后具有抗炎作用。然而，二氢杨梅素在 ICH 后小胶质细胞细胞焦亡和神经炎症中的作用尚不清楚。本研究旨在探讨二氢杨梅素对 ICH 小鼠模型中小胶质细胞细胞焦亡介导的神经炎症的影响，并探讨其潜在机制。在这项研究中，我们观察到二氢杨梅素治疗显著改善了神经行为表现，减少了 BBB 破坏和脑水含量。二氢杨梅素也明显减轻了 ICH 后血肿周围组织中小胶质细胞的激活和中性粒细胞浸润。在分子水平上，二氢杨梅素显著调节了 Rkip 的表达，并下调了 Nlrp3 炎性小体、GSDMD、caspase-1 和成熟的 IL-1β、TNF-α 和 MPO 等细胞焦亡分子和炎症细胞因子的表达。此外，二氢杨梅素治疗减少了 ICH 后 Caspase-1 阳性小胶质细胞和 GSDMD 阳性小胶质细胞的数量。相反，Rkip 特异性抑制剂 Locostatin 显著消除了二氢杨梅素的抗细胞焦亡和抗炎作用。此外，Asc 与 Rkip 的结合可以中断炎性小体的激活和组装。在机制上，通过下调 GSDMD、成熟的 IL-1β、TNF-α 和 MPO，Caspase-1 抑制剂 VX-765 抑制了脑损伤，并抑制了小胶质细胞细胞焦亡和神经炎症，基于用 Locostatin 处理 ICH。综上所述，二氢杨梅素通过上调 Rkip 表达减轻了小胶质细胞细胞焦亡和神经炎症，至少部分是通过 Asc/Caspase-1/GSDMD 通路实现的。因此，二氢杨梅素可能是一种减轻神经炎症的潜在药物，其对 ICH 的抗细胞焦亡作用。
