Ozanimod-Dependent Activation of SIRT3/NF-κB/AIM2 Pathway Attenuates Secondary Injury After Intracerebral Hemorrhage
Ozanimod-Dependent Activation of SIRT3/NF-κB/AIM2 Pathway Attenuates Secondary Injury After Intracerebral Hemorrhage
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DOI：
10.1007/s12035-022-03137-2
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发表时间：
2022-11
影响因子：
5.1
通讯作者：
Xiaoxi Li;Heyu Zhang;Wen-Fei Zheng;Jizhou Sun;Liyuan Wang;Zhiyi He
中科院分区：
文献类型：
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作者：
Xiaoxi Li;Heyu Zhang;Wen-Fei Zheng;Jizhou Sun;Liyuan Wang;Zhiyi He
脑出血（ICH）的特点是预后差，死亡率高。迄今为止，满意的治疗方法仍然有限，因此迫切需要开发更安全，更有效的处方。继发性炎症反应被认为是脑出血后神经功能恶化的加重因素。作为炎症感受器的一个组成部分，AIM 2在神经炎症过程中起着重要的作用。在这里，ozanimod，一种新的选择性鞘氨醇1-磷酸受体调节剂，已经获得了广泛的关注，它减轻了由此产生的神经炎症，并改善了ICH的功能恢复。在这项研究中，ozanimod通过减少血肿大小来改善ICH小鼠的神经功能。此外，ozanimod逆转了小胶质细胞和AIM 2炎性小体的激活，这通过利用Western印迹和酶联免疫吸附测定下调相关炎性蛋白和细胞因子（IL-1β、IL-6和TNF-α）以及上调SIRT 3得到证实。此外，我们发现ozanimod降低活化B细胞（NF-κB）的核因子κ轻链增强子表达。值得注意的是，脂多糖诱导的体外细胞实验证实，奥扎莫德的抗炎作用可以被SIRT 3抑制剂消除。总之，这些结果表明，ozanimod通过调节SIRT 3/NF-κB/AIM 2通路介导的AIM 2炎性体来减轻ICH诱导的继发性炎症反应。这表明ozanimod协调ICH诱导的神经炎症，并可能成为改善ICH预后的靶向治疗。
Intracerebral hemorrhage (ICH) is characterized by poor prognosis and high mortality rates. To date, satisfactory therapeutic approaches for ICH remain limited, so it is urgently needed to develop a safer and more effective prescription. Secondary inflammatory response has been acknowledged as an aggravating factor to neurological deterioration after ICH. As a component of inflammasome sensors, absent in melanoma 2 (AIM2) plays an important role in the neuroinflammation process. Here, ozanimod, a novel selective sphingosine 1-phosphate receptor modulator, has gained much attention, which alleviates the resultant neuroinflammation and improves functional recovery derived from ICH. In this study, ozanimod improved neurological functions of ICH mice via reduction of hematoma size. Furthermore, both microglial and AIM2 inflammasome activations were reversed by ozanimod, which are confirmed by the downregulation of related inflammatory proteins and cytokines (IL-1β, IL-6, and TNF-α), coupled with the upregulation of SIRT3, by leveraging the Western blot and enzyme-linked immunosorbent assay. Additionally, we find that ozanimod decreases nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) expression. Notably, in vitro cell experiments induced by lipopolysaccharide confirms that the anti-inflammatory effect of ozanimod could be abolished by the SIRT3 inhibitor. In conclusion, these results indicate that ozanimod mitigates ICH-induced secondary inflammatory responses by modulating AIM2 inflammasome mediated by SIRT3/NF-κB/AIM2 pathway. This demonstrates ozanimod orchestrates ICH-induced neuroinflammation and could be a targeted therapy for improving prognosis of ICH.