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

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.

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.

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.

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.