Yun Su1,2,3, Changhe Shi1,3, Tai Wang4, Chen Liu1,3, Jing Yang1,3, Shuyu Zhang5, Liyuan Fan1,2,3, Huimin Zheng1,2,3, Xinwei Li1,2,3, Haiyang Luo1,2,3, Shuo Zhang1,2,3, Zhengwei Hu1,2,3, Yu Fan1,3, Xiaoyan Hao1,3, Chenglin Zhang2,6, Bo Song1,3, Chengyuan Mao7,8,9,10, Yuming Xu11,12,13. 1. Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, No. 1 Eastern Jian-she Road, Zhengzhou, 450052, Henan, China. 2. The Academy of Medical Sciences of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China. 3. Henan Key Laboratory of Cerebrovascular Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China. 4. Department of Neurology, Nanyang Central Hospital, Nanyang, Henan, China. 5. Neuro-Intensive Care Unit, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China. 6. Sino-British Research Centre for Molecular Oncology, School of Basic Medical Sciences, National Centre for International Research in Cell and Gene Therapy, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China. 7. Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, No. 1 Eastern Jian-she Road, Zhengzhou, 450052, Henan, China. maochengyuan2015@126.com. 8. The Academy of Medical Sciences of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China. maochengyuan2015@126.com. 9. Henan Key Laboratory of Cerebrovascular Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China. maochengyuan2015@126.com. 10. Sino-British Research Centre for Molecular Oncology, School of Basic Medical Sciences, National Centre for International Research in Cell and Gene Therapy, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China. maochengyuan2015@126.com. 11. Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, No. 1 Eastern Jian-she Road, Zhengzhou, 450052, Henan, China. xuyuming@zzu.edu.cn. 12. Henan Key Laboratory of Cerebrovascular Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China. xuyuming@zzu.edu.cn. 13. NHC Key Laboratory of Prevention and Treatment of Cerebrovascular Diseases, Zhengzhou, Henan, China. xuyuming@zzu.edu.cn.
Abstract
BACKGROUND AND OBJECTIVES: Mounting evidence indicates the involvement of the innate immune system in Parkinson's disease (PD). Nevertheless, the implications of peripheral monocytes have not been fully elucidated. Although alpha-synuclein (α-synuclein) has been described as a pathological hallmark of PD, the proinflammatory effect of α-synuclein on monocytes is understudied. This study aimed to comprehensively characterize peripheral monocytes in PD patients and to investigate the proinflammatory magnitude of fibrillar α-synuclein. METHODS: Using flow cytometry, we explored the distribution of monocytic subpopulations. We also investigated the actions of peripheral monocytes in response to lipopolysaccharides (LPS) and to fibrillar α-synuclein stimuli by measuring inflammatory molecule levels in post-culture supernatants. RESULTS: Classical monocytes were enriched, in parallel with lower proportions of intermediate and nonclassical monocytes in patients with PD than in controls. Lower levels of TNF-α and IL-6 were spontaneously produced by unstimulated monocytes in patients with PD. LPS and fibrillar α-synuclein stimuli induced high levels of TNF-α, IL-1β, IL-6, and sCD163 in the PD and control groups. Strikingly, the fold induction of TNF-α and IL-6 was lower in patients with PD than that in normal controls under the same stimulation. CONCLUSION: Our results revealed a strong dysregulation of peripheral monocytes in PD patients, including subpopulation shifts and impaired response to specific stimuli, and the proinflammatory effect of α-synuclein on monocytes. Further studies are needed to clarify the specific mechanisms by which these immunological abnormalities are present in PD to open the possibility of immunoregulatory therapy.
BACKGROUND AND OBJECTIVES: Mounting evidence indicates the involvement of the innate immune system in Parkinson's disease (PD). Nevertheless, the implications of peripheral monocytes have not been fully elucidated. Although alpha-synuclein (α-synuclein) has been described as a pathological hallmark of PD, the proinflammatory effect of α-synuclein on monocytes is understudied. This study aimed to comprehensively characterize peripheral monocytes in PD patients and to investigate the proinflammatory magnitude of fibrillar α-synuclein. METHODS: Using flow cytometry, we explored the distribution of monocytic subpopulations. We also investigated the actions of peripheral monocytes in response to lipopolysaccharides (LPS) and to fibrillar α-synuclein stimuli by measuring inflammatory molecule levels in post-culture supernatants. RESULTS: Classical monocytes were enriched, in parallel with lower proportions of intermediate and nonclassical monocytes in patients with PD than in controls. Lower levels of TNF-α and IL-6 were spontaneously produced by unstimulated monocytes in patients with PD. LPS and fibrillar α-synuclein stimuli induced high levels of TNF-α, IL-1β, IL-6, and sCD163 in the PD and control groups. Strikingly, the fold induction of TNF-α and IL-6 was lower in patients with PD than that in normal controls under the same stimulation. CONCLUSION: Our results revealed a strong dysregulation of peripheral monocytes in PD patients, including subpopulation shifts and impaired response to specific stimuli, and the proinflammatory effect of α-synuclein on monocytes. Further studies are needed to clarify the specific mechanisms by which these immunological abnormalities are present in PD to open the possibility of immunoregulatory therapy.
Authors: William T Wissemann; Erin M Hill-Burns; Cyrus P Zabetian; Stewart A Factor; Nikolaos Patsopoulos; Bryan Hoglund; Cherie Holcomb; Ryan J Donahue; Glenys Thomson; Henry Erlich; Haydeh Payami Journal: Am J Hum Genet Date: 2013-10-31 Impact factor: 11.025
Authors: Cornelis Blauwendraat; Karl Heilbron; Costanza L Vallerga; Sara Bandres-Ciga; Rainer von Coelln; Lasse Pihlstrøm; Javier Simón-Sánchez; Claudia Schulte; Manu Sharma; Lynne Krohn; Ari Siitonen; Hirotaka Iwaki; Hampton Leonard; Alastair J Noyce; Manuela Tan; J Raphael Gibbs; Dena G Hernandez; Sonja W Scholz; Joseph Jankovic; Lisa M Shulman; Suzanne Lesage; Jean-Christophe Corvol; Alexis Brice; Jacobus J van Hilten; Johan Marinus; Johanna Eerola-Rautio; Pentti Tienari; Kari Majamaa; Mathias Toft; Donald G Grosset; Thomas Gasser; Peter Heutink; Joshua M Shulman; Nicolas Wood; John Hardy; Huw R Morris; David A Hinds; Jacob Gratten; Peter M Visscher; Ziv Gan-Or; Mike A Nalls; Andrew B Singleton Journal: Mov Disord Date: 2019-04-07 Impact factor: 10.338
Authors: Alexander Gerhard; Nicola Pavese; Gary Hotton; Federico Turkheimer; Meltem Es; Alexander Hammers; Karla Eggert; Wolfgang Oertel; Richard B Banati; David J Brooks Journal: Neurobiol Dis Date: 2005-09-21 Impact factor: 5.996
Authors: Taye H Hamza; Cyrus P Zabetian; Albert Tenesa; Alain Laederach; Jennifer Montimurro; Dora Yearout; Denise M Kay; Kimberly F Doheny; Justin Paschall; Elizabeth Pugh; Victoria I Kusel; Randall Collura; John Roberts; Alida Griffith; Ali Samii; William K Scott; John Nutt; Stewart A Factor; Haydeh Payami Journal: Nat Genet Date: 2010-08-15 Impact factor: 38.330
Authors: Mike A Nalls; Nathan Pankratz; Christina M Lill; Chuong B Do; Dena G Hernandez; Mohamad Saad; Anita L DeStefano; Eleanna Kara; Jose Bras; Manu Sharma; Claudia Schulte; Margaux F Keller; Sampath Arepalli; Christopher Letson; Connor Edsall; Hreinn Stefansson; Xinmin Liu; Hannah Pliner; Joseph H Lee; Rong Cheng; M Arfan Ikram; John P A Ioannidis; Georgios M Hadjigeorgiou; Joshua C Bis; Maria Martinez; Joel S Perlmutter; Alison Goate; Karen Marder; Brian Fiske; Margaret Sutherland; Georgia Xiromerisiou; Richard H Myers; Lorraine N Clark; Kari Stefansson; John A Hardy; Peter Heutink; Honglei Chen; Nicholas W Wood; Henry Houlden; Haydeh Payami; Alexis Brice; William K Scott; Thomas Gasser; Lars Bertram; Nicholas Eriksson; Tatiana Foroud; Andrew B Singleton Journal: Nat Genet Date: 2014-07-27 Impact factor: 38.330
Authors: C H Williams-Gray; R S Wijeyekoon; K M Scott; S Hayat; R A Barker; J L Jones Journal: J Neuroinflammation Date: 2018-05-28 Impact factor: 8.322