Dysregulation of peripheral monocytes and pro-inflammation of alpha-synuclein in Parkinson's disease

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 (alpha-synuclein) has been described as a pathological hallmark of PD, the proinflammatory effect of alpha-synuclein on monocytes is understudied. This study aimed to comprehensively characterize peripheral monocytes in PD patients and to investigate the proinflammatory magnitude of fibrillar alpha-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 alpha-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-alpha and IL-6 were spontaneously produced by unstimulated monocytes in patients with PD. LPS and fibrillar alpha-synuclein stimuli induced high levels of TNF-alpha, IL-1 beta, IL-6, and sCD163 in the PD and control groups. Strikingly, the fold induction of TNF-alpha 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 alpha-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.

Automated summary

This study comprehensively characterized peripheral monocytes in Parkinson's disease (PD) patients and investigated the proinflammatory effect of fibrillar alpha-synuclein. The results revealed dysregulation of peripheral monocytes in PD patients, including subpopulation shifts and impaired response to specific stimuli.