School of Public Health, Dalian Medical University, No. 9 W. Lvshun South Road, Dalian 116044, China; Department of Anesthesiology, Affiliated Zhongshan Hospital of Dalian University, Dalian 116023, China.
School of Public Health, Dalian Medical University, No. 9 W. Lvshun South Road, Dalian 116044, China.
Ecotoxicol Environ Saf. 2023 Nov 1;266:115550. doi: 10.1016/j.ecoenv.2023.115550. Epub 2023 Oct 11.
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.
小胶质细胞介导的慢性神经炎症与鱼藤酮诱导的认知能力下降有关，鱼藤酮是一种常用于农业的著名神经毒性农药。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，CR3 是小胶质细胞中高度表达的受体。鱼藤酮上调了小鼠海马和皮质区 CR3 的表达。CR3 缺乏显著改善了鱼藤酮诱导的认知障碍、神经退行性变和α-突触核蛋白的磷酸化（Ser129）。CR3 缺乏还减弱了鱼藤酮刺激的小胶质细胞 M1 激活。在小胶质细胞中，siRNA 介导的 CR3 敲低抑制了鱼藤酮诱导的小胶质细胞 M1 激活，而 LL-37 诱导的 CR3 激活则加剧了该激活。机制上，CR3 缺乏阻断了鱼藤酮诱导的核因子 κB（NF-κB）、信号转导和转录激活因子 1（STAT1）和 STAT3 信号通路的激活。药理学抑制 NF-κB 或 STAT3（但不是 STAT1）被证实可抑制鱼藤酮诱导的小胶质细胞 M1 激活。进一步研究表明，CR3 缺乏或敲低也减少了鱼藤酮诱导的 C3 的表达，C3 是 A1 星形胶质细胞的标志物，以及小胶质细胞 C1q、TNFα 和 IL-1α 的产生，这是激活的小胶质细胞诱导神经毒性 A1 星形胶质细胞的混合物，通过 NF-κB 和 STAT3 途径。最后，一种 CR3 的小分子调节剂即使在认知功能障碍确立后给药，也能有效缓解鱼藤酮引起的小鼠认知缺陷。总之，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，为与农药相关的帕金森病认知障碍的免疫发病机制提供了新的见解。
