Abstract
The immune system is activated in Parkinson's Disease (PD), as evidenced by neuroinflammatory changes within the brain as well as elevated immune markers in peripheral blood. Furthermore, inflammatory cytokine levels in the blood are associated with disease severity and rate of progression. However, the factors driving this immune response in PD are not well established. We investigated cell-extrinsic factors in systemic immune activation by using α-synuclein monomers and fibrils, as well as bacterial toxins, to stimulate peripheral blood mononuclear cells (PBMCs) derived from 31 patients and age/gender-matched controls. α-synuclein monomers or fibrils resulted in a robust cytokine response (as measured by supernatant cytokine concentrations and mRNA expression in cultured cells) in both PD and control PBMCs, similar to that induced by bacterial LPS. We found no PD vs. control differences in cytokine production, nor in mRNA expression. Levels of endotoxin within the recombinant α-synuclein used in these experiments were very low (0.2–1.3EU/mL), but nonetheless we found that comparable levels were sufficient to potentially confound our cytokine concentration measurements for a number of cytokines. However, α-synuclein monomers increased production of IL-1β and IL-18 to levels significantly in excess of those induced by low-level endotoxin. In conclusion, this study: (i) highlights the importance of accounting for low-level endotoxin in antigen-PBMC stimulation experiments; (ii) indicates that cell-extrinsic factors may be a major contributor to immune activation in PD; and (iii) suggests that α-synuclein may play a role in inflammasome-related cytokine production in the periphery.
Highlights
The immune system is known to be altered in Parkinson’s disease (PD)
Fibrillar αsynuclein has been shown to act via Toll-like receptor (TLR) and inflammasome pathways in monocytes leading to IL-1β production [12]
peripheral blood mononuclear cells (PBMCs) were cultured with LPS (n = 31 case-control pairs), and α-synuclein monomers and fibrils (n = 19 case-control pairs)
Summary
The immune system is known to be altered in Parkinson’s disease (PD). Whilst some of these changes may be secondary phenomena, a growing body of evidence suggests that the immune system may play a contributory role in the primary progression of PD [1, 2]. α-synuclein is the key protein implicated in the pathogenesis of PD, forming intracellular aggregates known as Lewy bodies [3]. Fibrillar αsynuclein has been shown to act via Toll-like receptor (TLR) and inflammasome pathways in monocytes leading to IL-1β production [12]. Other factors such as infections or translocation of bacterial toxins from the gut may contribute to inflammation in PD [21, 22]. In another study, production of IFNγ by LPS-stimulated PBMCs was lower in patients than controls, while IL-6, IL-1α, and IL-1ß levels were no different, but decreasing concentrations correlated worsened disease severity [24]. Given this ambiguity in the literature and the absence of any study investigating both α-synuclein and LPS stimulation of PBMCs in PD patients, we sought to understand how stimulation by α-synuclein monomers, fibrils, and LPS affects PBMC cytokine production in PD patients and matched controls
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