α-Synuclein-containing erythrocytic extracellular vesicles: essential contributors to hyperactivation of monocytes in Parkinson’s disease

Journal of Neuroinflammation

Robin Barry Chan¹  Zhenwei Yu²  Yufeng Wu³  Tao Feng⁴  Zongran Liu⁵  Ying Yang⁵  Xiaodan Liu⁵  Jing Zhang⁶  Zhijian Cai⁷ 

[1] AliveX Biotech, 200030, Shanghai, China;Beijing Neurosurgical Institute, Capital Medical University, 100050, Beijing, China;Department of Laboratory Medicine, Peking University Third Hospital, Peking University Health Science Center, Beijing, China;Department of Neurology, TianTan Hospital, Capital Medical University, 100050, Beijing, China;Department of Pathology, Peking University Health Science Center, 100191, Beijing, China;Department of Pathology, Zhejiang University School of Medicine and First Affiliated Hospital, 310002, Hangzhou, Zhejiang, China;National Health and Disease Human Brain Tissue Resource Center, Zhejiang University, 310002, Hangzhou, Zhejiang, China;School of Basic Medicine, Zhejiang University, 310002, Hangzhou, Zhejiang, China;

关键词: Extracellular vesicles;    RBC;    α-Synuclein;    Parkinson’s disease;    Monocytes;    LRRK2;   

DOI  :  10.1186/s12974-022-02413-1

来源: Springer

【 摘 要 】

BackgroundImmune system dysfunction, including higher levels of peripheral monocytes and inflammatory cytokines, is an important feature of Parkinson’s disease (PD) pathogenesis, although the mechanism underlying the process remains to be investigated. In the central nervous system, it is well-known that α-synuclein (α-syn), a key protein involved in PD, activates microglia potently, and it is also reported that α-syn exists in the peripheral system, especially in erythrocytes or red blood cells (RBC) at exceedingly high concentration. The current study focused on the possibility that RBC-derived α-syn mediates the sensitization of peripheral monocytes in PD patients.MethodsThe hyperactivation of monocytes was assessed quantitatively by measuring mRNA levels of typical inflammatory cytokines (including IL-1β, IL-6 and TNF-α) and protein levels of secreted inflammatory cytokines (including pro-inflammatory cytokines: IL-1β, IL-6, TNF-α, IL-8, IFN-γ, IL-2, and IL-12p70 and anti-inflammatory cytokines: IL-4, IL-10, and IL-13). Western blot, nanoparticle tracking analysis and electron microscopy were used to characterize RBC-derived extracellular vesicles (RBC-EVs). Inhibitors of endocytosis and leucine-rich repeat kinase 2 (LRRK2), another key protein involved in PD, were used to investigate how these two factors mediated the process of monocyte sensitization by RBC-EVs.ResultsIncreased inflammatory sensitization of monocytes was observed in PD patients and PD model mice. We found that α-syn-containing RBC-EVs isolated from PD model mice or free form oligomeric α-syn induced the inflammatory sensitization of THP-1 cells, and demonstrated that endocytosis was a requirement for this pathophysiological pathway. Furthermore, the hyperactivation of THP-1 cells induced by RBC-EVs was associated with increased LRRK2 production and kinase activity. The phenomenon of inflammatory sensitization of human monocytes and increased LRRK2 were also observed by the treatment of RBC-EVs isolated from PD patients.ConclusionsOur data provided new insight into how hyperactivation of monocytes occurs in PD patients, and identified the central role played by α-syn-containing RBC-EVs in this process.

【 授权许可】

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