Peripheral innate immune and bacterial signals relate to clinical heterogeneity in Parkinson’s disease

Ruwani S Wijeyekoon,Deborah Kronenberg-Versteeg,Kirsten M Scott,Shaista Hayat,Wei-Li Kuan,Jonathan R Evans,David P Breen,Gemma Cummins,Joanne L Jones,Menna R Clatworthy,R Andres Floto,Roger A Barker,Caroline H Williams-Gray

doi:10.1016/j.bbi.2020.01.018

Abstract

The innate immune system is implicated in Parkinson’s disease (PD), but peripheral in-vivo clinical evidence of the components and driving mechanisms involved and their relationship with clinical heterogeneity and progression to dementia remain poorly explored.We examined changes in peripheral innate immune-related markers in PD cases (n = 41) stratified according to risk of developing early dementia. ‘Higher Risk’(HR) (n = 23) and ‘Lower Risk’ (LR) (n = 18) groups were defined according to neuropsychological predictors and MAPT H1/H2 genotype, and compared to age, gender and genotype-matched controls. Monocyte subsets and expression of key surface markers were measured using flow cytometry. Serum markers including alpha-synuclein, inflammasome-related caspase-1 and bacterial translocation-related endotoxin were measured using quantitative immuno-based assays. Specific markers were further investigated using monocyte assays and validated in plasma samples from a larger incident PD cohort (n = 95).We found that classical monocyte frequency was elevated in PD cases compared to controls, driven predominantly by the HR group, in whom Toll-Like Receptor (TLR)4+ monocytes and monocyte Triggering Receptor Expressed on Myeloid cells-2 (TREM2) expression were also increased. Monocyte Human Leukocyte Antigen (HLA)-DR expression correlated with clinical variables, with lower levels associated with worse cognitive/motor performance. Notably, monocyte changes were accompanied by elevated serum bacterial endotoxin, again predominantly in the HR group.Serum alpha-synuclein and inflammasome-related caspase-1 were decreased in PD cases compared to controls regardless of group, with decreased monocyte alpha-synuclein secretion in HR cases. Further, alpha-synuclein and caspase-1 correlated positively in serum and monocyte lysates, and in plasma from the larger cohort, though no associations were seen with baseline or 36-month longitudinal clinical data.Principal Components Analysis of all monocyte and significant serum markers indicated 3 major components. Component 1 (alpha-synuclein, caspase-1, TLR2+ monocytes) differentiated PD cases and controls in both groups, while Component 2 (endotoxin, monocyte TREM2, alpha-synuclein) did so predominantly in the HR group. Component 3 (classical monocytes, alpha-synuclein) also differentiated cases and controls overall in both groups.These findings demonstrate that systemic innate immune changes are present in PD and are greatest in those at higher risk of rapid progression to dementia. Markers associated with PD per-se (alpha-synuclein, caspase-1), differ from those related to cognitive progression and clinical heterogeneity (endotoxin, TREM2, TLR4, classical monocytes, HLA-DR), with mechanistic and therapeutic implications. Alpha-synuclein and caspase-1 are associated, suggesting inflammasome involvement common to all PD, while bacterial translocation associated changes may contribute towards progression to Parkinson’s dementia. Additionally, HLA-DR-associated variations in antigen presentation/clearance may modulate existing clinical disease.

Highlights

Parkinson’s disease (PD) is clinically and pathologically heterogeneous (Rajput et al, 2009; Kehagia et al, 2010; Greenland et al, 2019)
We found that classical monocyte frequency was elevated in PD cases compared to controls, driven predominantly by the Higher Risk (HR) group, in whom Toll-Like Receptor (TLR)4+ monocytes and monocyte Triggering Receptor Expressed on Myeloid cells-2 (TREM2) expression were increased
TLR4+ monocytes constituted a higher percentage in PD compared to controls (W = −204, p = 0.0128), with statistical significance in the HR PD group (W = −124, p = 0.0004)

Summary

Introduction

Parkinson’s disease (PD) is clinically and pathologically heterogeneous (Rajput et al, 2009; Kehagia et al, 2010; Greenland et al, 2019). The biological drivers of heterogeneity in progression rates are not fully understood, and are likely to be complex, arising from interactions between genetic and environmental risk factors acting at multiple levels. Genetic studies have indicated associations between immune related gene variants and PD risk (e.g. Human Leukocyte Antigen-DR (HLA-DR), Triggering Receptor Expressed on Myeloid cells-2 (TREM2), Toll-like receptor 4 (TLR4) (Nalls et al, 2011; Hamza et al, 2010; Rayaprolu et al, 2013; Zhao et al, 2015)), while established PD related genes such as Leucine Rich Repeat Kinase 2 (LRRK2) have demonstrated involvement in the innate immune system (Lee et al, 2017a) and immunemediated conditions such as inflammatory bowel disease (Dzamko, 2017). Mice lacking mature T and B lymphocytes (Brochard et al, 2009) have decreased cell loss in a toxin-based model of PD and Central Nervous System (CNS) infiltration of C–C motif Chemokine Receptor2+ (CCR2+) monocytes (Harms et al, 2017) has been shown to influence disease pathology and expression

Results

Discussion

Conclusion