粒体自噬
炎症体
小胶质细胞
神经毒性
细胞生物学
线粒体分裂
线粒体ROS
神经炎症
帕金
活性氧
化学
线粒体
DNM1L型
半胱氨酸蛋白酶1
生物
炎症
生物化学
自噬
免疫学
细胞凋亡
医学
帕金森病
受体
有机化学
病理
疾病
毒性
作者
Wen-Qiong Wang,Rui Chang,Yan Wang,Liyan Hou,Qingshan Wang
标识
DOI:10.1016/j.neuro.2023.09.008
摘要
We recently revealed a pivotal role of NLRP3 inflammasome in the neurotoxicity induced by n-hexane, owing to its activation and release of pro-inflammatory cytokines. However, the mechanisms of how the activation of NLRP3 inflammasome was triggered by 2,5-hexanedione (HD), the toxic product of n-hexane metabolism, remain to be explored. Here, we investigated whether mitochondrial reactive oxygen species (mtROS) was involved in HD-elicited NLRP3 inflammasome activation in microglia. We demonstrated that exposure to HD at 4 and 8 mM elevated production of mtROS in BV2 microglia. Scavenging mtROS by Mito-TEMPO, an mtROS scavenger, dramatically reduced HD-induced NLRP3 expression, caspase-1 activation and interleukin-1β production, pointing a crucial role of mtROS in NLRP3 inflammasome activation. Mechanistic study revealed that HD intoxication promoted activation of mitophagy. HD induced expression of Beclin-1, LC3II, and two mitophagy-related proteins, i.e., Pink1 and Parkin and simultaneously, reduced p62 expression in both whole cell and isolated mitochondria of microglia. Furthermore, inhibition of mitophagy by 3-methyladenine (3-MA) greatly reduced production of mtROS, expression of mitochondrial fission-related proteins, dynamin-related protein 1 (Drp1) and fission protein 1 (Fis1) and activation of NLRP3 inflammasome in HD-intoxicated microglia. Blocking mitochondrial fission by Mdivi-1 also prevented HD-induced mtROS production and NLRP3 inflammasome activation in microglia. In conclusion, our data indicated that HD triggered activation of NLRP3 inflammasome through mitophagy-dependent mtROS production, offering an important insight for the immunopathogenesis of environmental toxins-induced neuroinflammation and neurotoxicity.
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