Bilirubin Induces A1-Like Reactivity of Astrocyte
Bilirubin Induces A1-Like Reactivity of Astrocyte
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DOI：
10.1007/s11064-022-03810-x
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发表时间：
2022-11-08
影响因子：
4.4
通讯作者：
Hua, Ziyu
中科院分区：
文献类型：
--
作者：
Li, Siyu;Huang, Hongmei;Hua, Ziyu
星形胶质细胞在胆红素神经毒性的发病机制中起重要作用，激活的星形胶质细胞可能是导致神经细胞死亡和组织损伤的神经炎症过程的潜在介质。最近的研究报道，激活的小胶质细胞可以诱导两种类型的反应性星形胶质细胞。A1星形胶质细胞可导致神经元死亡和突触损伤，以及吞噬功能受损。因此，本研究的目的是探讨未结合胆红素(UCB)诱导的A1样星形胶质细胞是否呈现神经炎性类型及其潜在的调控机制。在这项研究中，原代大脑皮层星形胶质细胞被脐带血作用于体外。检测补体成分3(C3)、S100钙结合蛋白A10(S100A10)、核因子kappaB(NF-kappa B)、NLRP3、活化caspase-1、Gasdermin D N端(GSDMD-N)、PSD95、突触素(SYP)、IL-1β和IL-18的转录水平以及UCB作用后星形胶质细胞的存活率。结果表明，脐带血刺激后C3表达增加，S100A10表达减少，A1样星形胶质细胞有功能表达。同时，脐带血刺激后，核因子-kappaB和caspase-1通路被激活。加入转录结合域转录激活因子反式激活因子(TAT-NBD)和caspase-1特异性抑制剂VX-765后，星形胶质细胞和神经元的存活率增加，而C3、NF-kappa B、NLRP3、活化的caspase-1和GSDMD-N的蛋白表达降低，IL-1β和IL-18的mRNA水平降低。因此，我们得出结论，脐带血能够刺激A1样星形胶质细胞的激活。抑制核因子-kappaB和半胱氨酸天冬氨酸氨基转移酶-1可减轻A1样星形胶质细胞的数量，发挥抗炎保护作用。
Astrocytes play an important role in the pathogenesis of bilirubin neurotoxicity, and activated astrocytes might be potential mediators of neuroinflammation processes contributing to neuronal cell death and tissue injury. Recent studies have reported that activated microglia induce two types of reactive astrocytes. A1 astrocytes could cause neuronal death and synaptic damage, as well as impaired phagocytosis. Therefore, the purpose of this study was to investigate whether unconjugated bilirubin (UCB)-induced A1-like astrocytes take on a neuroinflammation type and the underlying regulatory mechanisms. In this study, primary cortical astrocytes were treated with UCB in vitro. We detected the expression of complement component 3 (C3), S100 calcium binding protein A10 (S100A10), nuclear factor kappa B (NF-kappa B), NLR family pyrin domain containing 3 (NLRP3), activated caspase-1, gasdermin D N-terminal (GSDMD-N), PSD95, synaptophysin (SYP), the transcription levels of interleukin (IL)-1 beta and IL-18, and the survival rate of astrocytes after UCB treatment. The results showed that an increase in C3 was accompanied by a decrease in S100A10, and that A1-like astrocytes were functionally expressed after UCB stimulation. Meanwhile, the NF-kappa B and caspase-1 pathways were activated after UCB stimulation. After adding the NF-kappa B-specific inhibitor trans-activator of transcriptional-NEMO-binding domain (TAT-NBD) and caspase-1 specific inhibitor VX-765, the survival rate of astrocytes and neurons increased, whereas the protein expression of C3, NF-kappa B, NLRP3, activated caspase-1, and GSDMD-N decreased, and the mRNA levels of IL-1 beta and IL-18 reduced. Thus, we concluded that UCB stimulates the activation of A1-like astrocytes. Inhibition of NF-kappa B and caspase-1 alleviated A1-like astrocytes and exerted anti-inflammatory protective effects.