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.
Redox Biol. 2024 Nov;77:103369. doi: 10.1016/j.redox.2024.103369. Epub 2024 Sep 24.
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.
补体受体 3（CR3）在小胶质细胞中的激活有助于神经退行性疾病，包括帕金森病（PD）的神经变性。然而，对于 CR3 如何介导神经元损伤的机制知识仍不清楚。在这项研究中，发现 CR3 及其配体 iC3b 和 ICAM-1 的表达在鱼藤酮 PD 小鼠的中脑中上调，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积累，并恢复了对鱼藤酮的铁代谢标志物的表达。此外，与 WT 小鼠相比，CR3 基因敲除小鼠的多巴胺能神经元脂质过氧化、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在体外也得到了证实。机制研究表明，神经元中铁的积累而不是小胶质细胞与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是必要的。在细胞培养系统中，小胶质细胞 CR3 沉默显著抑制了神经元中铁的沉积，这伴随着脂质过氧化和神经退行性变的减轻。此外，通过 NOX2 从激活的小胶质细胞释放的 ROS 被鉴定为与小胶质细胞 CR3 介导的铁积累和随后的神经元铁死亡偶联。最后，发现外源性铁的补充恢复了 CR3 小鼠对鱼藤酮诱导的神经元铁死亡的敏感性。总之，我们的研究结果表明，小胶质细胞 CR3 通过 NOX2 介导的铁积累调节神经元铁死亡，为神经退行性疾病的免疫发病机制提供了新的观点。
