Microglial CR3 promotes neuron ferroptosis via NOX2-mediated iron deposition in rotenone-induced experimental models of Parkinson's disease
Qinghui Wang,
Jianing Liu,
Yu Zhang,
Zhen Li,
Zirui Zhao,
Wanwei Jiang,
Jie Zhao,
Liyan Hou,
Qingshan Wang
Affiliations
Qinghui Wang
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
Jianing Liu
School of Public Health, Dalian Medical University, No. 9 W. Lvshun South Road, Dalian, 116044, China
Yu Zhang
National-Local Joint Engineering Research Center for Drug-Research and Development (R & D) of Neurodegenerative Diseases, Dalian Medical University, No. 9 W. Lvshun South Road, Dalian, 116044, China
Zhen Li
National-Local Joint Engineering Research Center for Drug-Research and Development (R & D) of Neurodegenerative Diseases, Dalian Medical University, No. 9 W. Lvshun South Road, Dalian, 116044, China
Zirui Zhao
National-Local Joint Engineering Research Center for Drug-Research and Development (R & D) of Neurodegenerative Diseases, Dalian Medical University, No. 9 W. Lvshun South Road, Dalian, 116044, China
Wanwei Jiang
Department of Anesthesiology, Affiliated Zhongshan Hospital of Dalian University, Dalian, 116023, China
Jie Zhao
National-Local Joint Engineering Research Center for Drug-Research and Development (R & D) of Neurodegenerative Diseases, Dalian Medical University, No. 9 W. Lvshun South Road, Dalian, 116044, China
Liyan Hou
The Library of Dalian Medical University, Dalian Medical University, No. 9 W. Lvshun South Road, Dalian, 116044, China; Corresponding author.
Qingshan Wang
School of Public Health, Dalian Medical University, No. 9 W. Lvshun South Road, Dalian, 116044, China; National-Local Joint Engineering Research Center for Drug-Research and Development (R & D) of Neurodegenerative Diseases, Dalian Medical University, No. 9 W. Lvshun South Road, Dalian, 116044, China; Corresponding author. School of Public Health, Dalian Medical University, No. 9 W. Lvshun South Road, Dalian, 116044, China.
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.
