HMGB1 Mediates Paraquat-Induced Neuroinflammatory Responses via Activating RAGE Signaling Pathway
HMGB1 Mediates Paraquat-Induced Neuroinflammatory Responses via Activating RAGE Signaling Pathway
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HMGB1 通过激活 RAGE 信号通路介导百草枯诱导的神经炎症反应
DOI：
10.1007/s12640-019-00148-1
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发表时间：
2020-04-01
影响因子：
3.7
通讯作者：
Yang, Huifang
中科院分区：
文献类型：
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作者：
Huang, Min;Guo, Muzhen;Yang, Huifang
百草枯(Paraquat，PQ)是一种具有广泛特征的神经毒物，已被普遍认为是帕金森病(Parkinson‘s Disease，PD)病因学的环境因素之一。尽管有直接证据表明PQ可以在中枢神经系统中诱导炎症反应，但PQ对神经免疫相互作用的潜在不良影响却很少被研究。高迁移率族蛋白1(HMGB1)已被证明与PD相关的神经炎症有关；然而，HMGB1是否以及如何在神经系统中对PQ暴露起调节作用仍不清楚。因此，本研究在SH-SY5Y细胞中研究了HMGB1和PQ暴露之间的潜在联系，这是一个成熟的PD研究的体外模型。我们观察到，HMGB1随PQ暴露浓度和时间的增加而显著增加，并且升高的HMGB1可以转运到胞浆中，然后释放到SH-SY5Y细胞的胞外环境。HMGB1基因敲除可抑制RAGE-P38-NF-kappaB信号通路的激活，抑制炎症细胞因子如TNF-α和IL-6的表达。这些结果提示，HMGB1可能通过激活RAGE信号通路和促进神经炎性反应参与PQ诱导的神经元死亡。
Paraquat (PQ), a widely characterized neurotoxicant, has been generally accepted as one of the environmental factors in the etiology of Parkinson's disease (PD). Despite the direct evidence that PQ could induce inflammatory responses in central nervous system, the putative adverse effects of PQ on the neuroimmune interactions have rarely been investigated. High-mobility group box 1 (HMGB1) has been proven to be relevant to the neuroinflammation involved in PD; however, whether and how HMGB1 exerts modulatory effects in nervous system upon PQ exposure remain elusive. Therefore, the present study investigated the underlying association between HMGB1 and PQ exposure in SH-SY5Y cells, which is a well-established in vitro model for PD research. We observed that HMGB1 was markedly increased in a concentration and time-dependent manner upon PQ exposure, and the elevated HMGB1 could be translocated into cytosol and then released to the extracellular milieu of SH-SY5Y cells. Knockdown of HMGB1 inhibited the activation of RAGE-P38-NF-kappa B signaling pathway and the expression of inflammation cytokines such as TNF-alpha and IL-6. These results suggested that HMGB1 is involved in the PQ-induced neuron death via activating RAGE signaling pathways and promoting neuroinflammatory responses.