Complement receptor 3-mediated neurotoxic glial activation contributes to rotenone-induced cognitive decline in mice.
Complement receptor 3-mediated neurotoxic glial activation contributes to rotenone-induced cognitive decline in mice.
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DOI：
10.1016/j.ecoenv.2023.115550
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发表时间：
2023-10
影响因子：
6.8
通讯作者：
Qinghui Wang;Zhengzheng Ruan;Lu Jing;Ziyang Guo;Xiaomeng Zhang;Jianing Liu;Lu Tian;Wei Sun-Wei
中科院分区：
文献类型：
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作者：
Qinghui Wang;Zhengzheng Ruan;Lu Jing;Ziyang Guo;Xiaomeng Zhang;Jianing Liu;Lu Tian;Wei Sun-Wei
小胶质细胞介导的慢性神经炎症与鱼藤酮引起的认知能力下降有关，鱼藤酮是一种众所周知的用于农业的神经毒性农药。然而，其机制尚不清楚。本研究旨在阐明补体受体3 （CR3）在鱼藤酮诱导的认知缺陷中的作用。鱼藤酮上调小鼠海马和皮质区CR3的表达。CR3缺乏可显著改善鱼藤酮诱导的小鼠认知障碍、神经变性和α-突触核蛋白磷酸化（Ser129）。CR3缺乏也会减弱鱼藤酮刺激的小胶质细胞M1的激活。在小胶质细胞中，sirna介导的CR3下调受阻，而LL-37诱导的CR3激活加剧了鱼藤酮诱导的小胶质M1激活。机制上，CR3缺乏阻断鱼藤酮诱导的核因子κB （NF-κB）、转录信号转导和激活因子1 （STAT1）和STAT3信号通路的激活。药理抑制NF-κB或STAT3而非STAT1可抑制鱼藤酮引起的小胶质细胞M1的激活。进一步的研究表明，CR3缺乏或敲低还会降低鱼藤酮诱导的A1星形胶质细胞标志物C3的表达，以及激活的小胶质细胞通过NF-κB和STAT3途径诱导神经毒性A1星形胶质细胞的小胶质细胞C1q、TNFα和IL-1α的产生。最后，一种CR3的小分子调节剂有效地减轻了鱼藤酮引起的认知缺陷，即使是在认知功能障碍建立后给药。综上所述，我们的研究结果表明，CR3是介导鱼藤酮处理小鼠神经毒性胶质细胞激活和随后认知障碍的关键因素，为农药相关帕金森病认知障碍的免疫发病机制提供了新的见解。
Microglia-mediated chronic neuroinflammation has been associated with cognitive decline induced by rotenone, a well-known neurotoxic pesticide used in agriculture. However, the mechanisms remain unclear. This work aimed to elucidate the role of complement receptor 3 (CR3), a highly expressed receptor in microglia, in cognitive deficits induced by rotenone. Rotenone up-regulated the expression of CR3 in the hippocampus and cortex area of mice. CR3 deficiency markedly ameliorated rotenone-induced cognitive impairments, neurodegeneration and phosphorylation (Ser129) of α-synuclein in mice. CR3 deficiency also attenuated rotenone-stimulated microglial M1 activation. In microglial cells, siRNA-mediated knockdown of CR3 impeded, while CR3 activation induced by LL-37 exacerbated, rotenone-induced microglial M1 activation. Mechanistically, CR3 deficiency blocked rotenone-induced activation of nuclear factor κB (NF-κB), signal transducer and activator of transcription 1 (STAT1) and STAT3 signaling pathways. Pharmacological inhibition of NF-κB or STAT3 but not STAT1 was confirmed to suppress microglial M1 activation elicited by rotenone. Further study revealed that CR3 deficiency or knockdown also reduced rotenone-induced expression of C3, an A1 astrocyte marker, and production of microglial C1q, TNFα and IL-1α, a cocktail for activated microglia to induce neurotoxic A1 astrocytes, via NF-κB and STAT3 pathways. Finally, a small molecule modulator of CR3 efficiently mitigated rotenone-elicited cognitive deficits in mice even administered after the establishment of cognitive dysfunction. Taken together, our findings demonstrated that CR3 is a key factor in mediating neurotoxic glial activation and subsequent cognitive impairments in rotenone-treated mice, giving novel insights into the immunopathogenesis of cognitive impairments in pesticide-related Parkinsonism.