百草枯诱导的神经免疫毒性:失调的小胶质抗原加工和线粒体激活机制。

IF 5.4 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Ge Shi , Kaidong Wang , Qi Liu , Chenyang Wu , Qianrong Zhang , Yuan Ma , Ai Qi , Min Huang
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引用次数: 0

摘要

百草枯(PQ)具有神经毒性。在日常生活中,PQ暴露主要通过慢性和微量途径发生,诱发进行性神经元损伤或神经元突触丧失。此前,线粒体功能障碍是一个关键的潜在机制。新出现的证据表明,由小胶质细胞激活和t细胞浸润介导的神经炎症可能会加速神经元变性。虽然抗原呈递是t细胞浸润和功能激活的必要先决条件,但线粒体损伤和小胶质细胞抗原呈递失调之间的潜在关联仍未被探索。在这项研究中,我们最初从CTD数据库中确定了百草枯相关的靶基因簇。GO和KEGG的富集分析揭示了帕金森病的途径和线粒体过程。此外,我们建立了C57BL/6J(♂)小鼠连续1次/d注射PQ (1.25 mg/kg)以模拟早期神经毒性的时间依赖模型。对于老鼠来说,神经行为症状表现为学习和记忆能力的下降。病理上,以小胶质细胞活化和t细胞浸润为主的神经炎症反应先于可观察到的突触丧失。这与小胶质细胞的两个不同过程相关:1)表面趋化因子表达上调(CCL2、CCL3、CCL4、CCL5), 2)抗原识别、吞噬和递呈机制增强(TLR4、LAMP2、MHC II),促进CD4+/CD8+ t细胞募集。值得注意的是,α-突触核蛋白聚集体可能作为触发小胶质线粒体应激反应的抗原,线粒体蛋白酶(LONP1, CLPP, HTRA2)的表达改变证明了这一点。值得注意的是,白藜芦醇有效地恢复了BV-2小胶质细胞线粒体稳态和正常化抗原呈递。这项研究表明,小胶质细胞线粒体失调介导异常抗原呈递,从而驱动神经炎症级联反应。并为化学神经毒性提供了新的和潜在的机制见解。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Paraquat induced neuro-immunotoxicity: Dysregulated microglial antigen processing and mitochondrial activated mechanisms
Paraquat (PQ) is characterized by neurotoxicity. In daily life, PQ exposure mainly occurs through chronic and trace pathways, which induce progressive neuronal damage or neuronal synaptic loss. Previously, mitochondrial dysfunction was a critical underlying mechanism. Emerging evidence suggests that neuroinflammation mediated by microglial activation and T-cell infiltration may trigger accelerated neuronal degeneration. While antigen presentation constitutes an essential prerequisite for T-cell infiltration and functional activation, the potential association between mitochondrial impairment and microglial antigen presentation dysregulation remains unexplored. In this study, we initially identified paraquat-associated target gene clusters from the CTD database. Following the enrichment analyses of GO and KEGG revealed Parkinson's disease pathways and mitochondrial processes. Further, we constructed a time-dependent model for C57BL/6J (♂) mice continuously treated with PQ (1.25 mg/kg) once/day to imitate early-stage neurotoxicity. For mice, neurobehavioral symptoms showed a decrease in learning and memory abilities. Pathologically, the neuroinflammatory response dominated by microglial activation and T-cell infiltration preceded observable synaptic loss. This correlated with microglial two distinct processes: 1) upregulated surface chemokine expression (CCL2, CCL3, CCL4, CCL5), and 2) enhanced antigen recognition, phagocytosis, and presentation machinery (TLR4, LAMP2, MHC II), facilitating CD4+/CD8+ T-cell recruitment. Notably, α-synuclein aggregates may act as antigens triggering microglial mitochondrial stress responses, as evidenced by altered expression of mitochondrial proteases (LONP1, CLPP, HTRA2). Remarkably, resveratrol effectively restored BV-2 microglial mitochondrial homeostasis and normalized antigen presentation. This study demonstrated that microglial mitochondrial dysregulation mediates aberrant antigen presentation, thereby driving neuroinflammatory cascades. And provides novel and potential mechanistic insights into chemical neurotoxicity.
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来源期刊
CiteScore
7.70
自引率
3.90%
发文量
410
审稿时长
36 days
期刊介绍: Chemico-Biological Interactions publishes research reports and review articles that examine the molecular, cellular, and/or biochemical basis of toxicologically relevant outcomes. Special emphasis is placed on toxicological mechanisms associated with interactions between chemicals and biological systems. Outcomes may include all traditional endpoints caused by synthetic or naturally occurring chemicals, both in vivo and in vitro. Endpoints of interest include, but are not limited to carcinogenesis, mutagenesis, respiratory toxicology, neurotoxicology, reproductive and developmental toxicology, and immunotoxicology.
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