Benzene metabolites trigger pyroptosis and contribute to haematotoxicity via TET2 directly regulating the Aim2/Casp1 pathway
Benzene metabolites trigger pyroptosis and contribute to haematotoxicity via TET2 directly regulating the Aim2/Casp1 pathway
复制标题
苯代谢物通过 TET2 直接调节 Aim2/Casp1 通路触发细胞焦亡并导致血液毒性
DOI：
10.1016/j.ebiom.2019.08.056
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发表时间：
2019-09-01
期刊：
影响因子：
11.1
通讯作者：
Gao, Ai
中科院分区：
文献类型：
--
作者：
Guo, Xiaoli;Zhong, Wen;Gao, Ai
背景：长期低浓度苯暴露可导致造血功能抑制。然而，其潜在的机制仍然不清楚，特别是由早期效应分子介导的。在此，我们首次在mRNA微阵列中发现，在对照组、低剂量苯暴露组和慢性苯中毒组中，在低剂量苯暴露工人中证实了Casp 1和MS的表达，并伴有强效促炎性IL 1 β的升高。体外研究表明，苯代谢产物通过激活Aim 2/Casp 1通路诱导AHH-1细胞凋亡，并增加GSDMD的表达。TET 2在体内外的表达均升高，且与IL 1 β呈正相关。此外，我们还证实了1.4-BQ引起的细胞凋亡可以通过RNAi或TET 2抑制剂DMOG预处理来改善。研究结果：苯暴露可以通过TET 2直接调节Aim 2/Casp 1信号通路引起细胞凋亡，从而引起血液毒性。苯代谢产物通过激活Aim 2/Casp 1途径诱导细胞死亡，该途径可由Tet 2过表达调节。Tet 2可能是一个潜在的风险因素，并与苯相关疾病的发展有关。(C)2019作者由爱思唯尔公司出版
Background: Long term low-close benzene exposure leads to the inhibition of haematopoiesis. However, the underlying mechanisms remained poorly defined, especially mediated by early effector molecules.Methods: Here, we first found in mRNA microarray that pyroptotic classic genes (Caspl, 4, 5, and IL1 beta) were upregulated and represented dose-dependent differential expression in controls, low-dose benzene-exposed and chronic benzene-poisoned workers, and the expression of Casp1 and MS were confirmed in low-dose benzene-exposed workers and was accompanied with elevated potent proinflammatory IL1 beta. In vitro studies showed that benzene metabolites induced AHH-1 cell pyroptosis through activating Aim2/Casp1 pathway with the increased expression of GSDMD. Meanwhile, TET2 overexpression was elevated in vivo and in vitro and it was positively correlated with IL1 beta. Further, we verified that pyroptosis caused by 1.4-BQ could be ameliorated in vitro by RNAi or pretreatment with Dimethyloxalylglycine (DMOG), the inhibitor of TET2.Findings: Exposure to benzene can trigger pyroptosis via TET2 directly regulating the Aim2/Casp1 signaling pathway to cause haematotoxicity.Interpretation: Benzene metabolites induced pyroptotic cell death through activation of the Aim2/Casp1 pathway which can be regulated by Tet2 overexpression. Tet2 may be a potential risk factor and is implicated in the development of benzene-related diseases. (C) 2019 The Authors. Published by Elsevier B.V.