| Title | alpha-Synuclein-containing erythrocytic extracellular vesicles: essential contributors to hyperactivation of monocytes in Parkinson's disease |
| Authors | Liu, Zongran Chan, Robin Barry Cai, Zhijian Liu, Xiaodan Wu, Yufeng Yu, Zhenwei Feng, Tao Yang, Ying Zhang, Jing |
| Affiliation | Peking Univ, Dept Pathol, Hlth Sci Ctr, Beijing 100191, Peoples R China AliveX Biotech, Shanghai 200030, Peoples R China Zhejiang Univ, Sch Basic Med, Hangzhou 310002, Zhejiang, Peoples R China Peking Univ Third Hosp, Dept Lab Med, Hlth Sci Ctr, Beijing, Peoples R China Capital Med Univ, Beijing Neurosurg Inst, Beijing 100050, Peoples R China Capital Med Univ, TianTan Hosp, Dept Neurol, Beijing 100050, Peoples R China Zhejiang Univ, Dept Pathol, Sch Med, Hangzhou 310002, Zhejiang, Peoples R China Zhejiang Univ, Affiliated Hosp 1, Hangzhou 310002, Zhejiang, Peoples R China Zhejiang Univ, Natl Hlth & Dis Human Brain Tissue Resource Ctr, Hangzhou 310002, Zhejiang, Peoples R China |
| Keywords | RED-BLOOD-CELLS SUBSTANTIA-NIGRA POTENTIAL BIOMARKER ALZHEIMERS-DISEASE REACTIVE MICROGLIA ENDOCYTOSIS NEURODEGENERATION CHOLESTEROL RECRUITMENT AUTOIMMUNE |
| Issue Date | 22-Feb-2022 |
| Publisher | JOURNAL OF NEUROINFLAMMATION |
| Abstract | Background: Immune 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 alpha-synuclein (alpha-syn), a key protein involved in PD, activates microglia potently, and it is also reported that alpha-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 alpha-syn mediates the sensitization of peripheral monocytes in PD patients. Methods: The hyperactivation of monocytes was assessed quantitatively by measuring mRNA levels of typical inflammatory cytokines (including IL-1 beta, IL-6 and TNF-alpha) and protein levels of secreted inflammatory cytokines (including pro-inflammatory cytokines: IL-1 beta, IL-6, TNF-alpha, IL-8, IFN-gamma, 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. Results: Increased inflammatory sensitization of monocytes was observed in PD patients and PD model mice. We found that alpha-syn-containing RBC-EVs isolated from PD model mice or free form oligomeric alpha-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. Conclusions: Our data provided new insight into how hyperactivation of monocytes occurs in PD patients, and identified the central role played by alpha-syn-containing RBC-EVs in this process. |
| URI | http://hdl.handle.net/20.500.11897/638420 |
| DOI | 10.1186/s12974-022-02413-1 |
| Indexed | SCI(E) |
| Appears in Collections: | 第三医院 |
