The activation of complement receptor 3 (CR3) in microglia contributes to neurodegeneration in neurological disorders, including Parkinson's disease (PD). However, it remains unclear for mechanistic knowledge on how CR3 mediates neuronal damage. In this study, the expression of CR3 and its ligands iC3b and ICAM-1 was found to be up-regulated in the midbrain of rotenone PD mice, which was associated with elevation of iron content and disruption of balance of iron metabolism proteins. Interestingly, genetic deletion of CR3 blunted iron accumulation and recovered the expression of iron metabolism markers in response to rotenone. Furthermore, reduced lipid peroxidation, ferroptosis of dopaminergic neurons and neuroinflammation were detected in rotenone-lesioned CR3−/− mice compared with WT mice. The regulatory effect of CR3 on ferroptotic death of dopaminergic neurons was also mirrored in vitro. Mechanistic study revealed that iron accumulation in neuron but not the physiological contact between microglia and neurons was essential for microglial CR3-regulated neuronal ferroptosis. In a cell-culture system, microglial CR3 silence significantly dampened iron deposition in neuron in response to rotenone, which was accompanied by mitigated lipid peroxidation and neurodegeneration. Furthermore, ROS released from activated microglia via NOX2 was identified to couple microglial CR3-mediated iron accumulation and subsequent neuronal ferroptosis. Finally, supplementation with exogenous iron was found to recover the sensitivity of CR3−/− mice to rotenone-induced neuronal ferroptosis. Altogether, our findings suggested that microglial CR3 regulates neuron ferroptosis through NOX2 -mediated iron accumulation in experimental Parkinsonism, providing novel points of the immunopathogenesis of neurological disorders.

中文翻译：

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在鱼藤酮诱导的帕金森病实验模型中，小胶质细胞 CR3 通过 NOX2 介导的铁沉积促进神经元铁死亡


小胶质细胞中补体受体 3 （CR3） 的激活会导致神经系统疾病的神经退行性变，包括帕金森病 （PD）。然而，关于 CR3 如何介导神经元损伤的机制知识仍不清楚。本研究发现鱼藤酮 PD 小鼠中脑中 CR3 及其配体 iC3b 和 ICAM-1 的表达上调，这与铁含量升高和铁代谢蛋白平衡破坏有关。有趣的是，CR3 的基因缺失减弱了铁的积累，并恢复了响应鱼藤酮的铁代谢标志物的表达。此外，与 WT 小鼠相比，在鱼藤酮损伤的 CR3 −/- 小鼠中检测到脂质过氧化、多巴胺能神经元铁死亡和神经炎症减少。CR3 对多巴胺能神经元铁死亡的调节作用也在体外得到反映。机制研究表明，铁在神经元中的积累而不是小胶质细胞和神经元之间的生理接触对于小胶质细胞 CR3 调节的神经元铁死亡至关重要。在细胞培养系统中，小胶质细胞 CR3 沉默响应鱼藤酮而显着抑制了神经元中的铁沉积，这伴随着减轻的脂质过氧化和神经退行性变。此外，经 NOX2 从活化的小胶质细胞释放的 ROS 被鉴定为偶联小胶质细胞 CR3 介导的铁积累和随后的神经元铁死亡。最后，发现补充外源性铁可以恢复 CR3 −/− 小鼠对鱼藤酮诱导的神经元铁死亡的敏感性。 总而言之，我们的研究结果表明，小胶质细胞 CR3 通过实验性帕金森病中 NOX2 介导的铁积累调节神经元铁死亡，为神经系统疾病的免疫发病机制提供了新的点。