The role of natural killer cells in Parkinson’s disease

Earls, Rachael H.; Lee, Jae‐Kyung

doi:10.1038/s12276-020-00505-7

Cited by 55 publications

(41 citation statements)

References 134 publications

(206 reference statements)

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“…Thus, changes in the expression levels of CD11b and CCR2 in iRBD supports a role for these proteins in the neurodegenerative process in synucleinopathies. Interestingly, CCL2 can also recruit NK cells (29), which are found in PD brain (30) and increased in PD blood (31). The iRBD patients had increased mature NK cells, which constitute those of higher CD16 expression and that possess cytotoxic capacity (29).…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, CCL2 can also recruit NK cells (29), which are found in PD brain (30) and increased in PD blood (31). The iRBD patients had increased mature NK cells, which constitute those of higher CD16 expression and that possess cytotoxic capacity (29). Interestingly, it is suggested that NK cells might have a protective role by clearing a-syn (30).…”

Section: Discussionmentioning

confidence: 99%

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Monocyte markers correlate with immune and neuronal brain changes in REM sleep behavior disorder

Farmen

Nissen

Stokholm

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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Synucleinopathies are neurodegenerative diseases with both central and peripheral immune responses. However, whether the peripheral immune changes occur early in disease and their relation to brain events is yet unclear. Isolated rapid-eye-movement (REM) sleep behavior disorder (iRBD) can precede synucleinopathy-related parkinsonism and provides a prodromal phenotype to study early Parkinson's disease events. In this prospective case-control study, we describe monocytic markers in a cohort of iRBD patients that were associated with the brain-imaging markers of inflammation and neuronal dysfunction. Using 11C-PK11195 positron emission tomography (PET), we previously showed increased immune activation in the substantia nigra of iRBD patients, while 18F-DOPA PET detected reduced putaminal dopaminergic function. Here we describe that patients’ blood monocytic cells showed increased expression of CD11b, while HLA-DR expression was decreased compared to healthy controls. The iRBD patients had increased classical monocytes and mature natural killer cells. Remarkably, the levels of expression of Toll-like receptor 4 (TLR4) on blood monocytes in iRBD patients were positively correlated with nigral immune activation measured by 11C-PK11195 PET and negatively correlated with putaminal 18F-DOPA uptake; the opposite was seen for the percentage of CD163+ myeloid cells. This suggesting a deleterious role for TLR4 and, conversely, a protective one for the CD163 expression. We show an association between peripheral blood monocytes and brain immune and dopaminergic changes in a synucleinopathy-related disorder, thus suggesting a cross-talk among periphery and brain during the disease.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Monocyte markers correlate with immune and neuronal brain changes in REM sleep behavior disorder

Farmen

Nissen

Stokholm

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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“…This upregulation suggests NK cell activation and that the cells are more prone to kill senescent cells, e.g. those burdened with α-syn (24).…”

Section: Resultsmentioning

confidence: 99%

“…Hence, the increased expression of CD16 on NK cells might contribute to the neurodegeneration mediated by the adaptive immune response. However, NK cells can also clear α-syn (44), thus they seem relevant for balancing the neuroprotective and neurodegenerative immune processes.…”

Section: Discussionmentioning

confidence: 99%

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Changes in CD163+, CD11b+, and CCR2+ peripheral monocytes relate to Parkinson’s disease and cognition

Nissen¹,

Farmen²,

Gjelstrup³

et al. 2021

Preprint

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Background: Alpha-synuclein aggregates and accumulation are associated with immune activation and neurodegeneration in Parkinson's disease. The immune activation is not only dependent on the brain-resident microglial cells but also involves peripheral immune cells, such as mononuclear phagocytes including monocytes and dendritic cells, found in the blood as well as infiltrated into the brain. Understanding the involvement of the peripheral immune component in Parkinson's disease is essential for the development of immunomodulatory treatment, which might modify disease progression. We aimed to study the profile of circulating mononuclear phagocytes in early- and late-stage Parkinson's disease by analyzing surface-expressed molecules related to phagocytosis, alpha-synuclein sensing, and tissue-migration. Methods: Multi-color flow cytometry on peripheral mononuclear cells from cross-sectional samples of 80 gender-balance individuals with early- and late-stage sporadic Parkinson's disease, and 29 controls, as well as longitudinal samples from seven patients and one control. Cells were delineated into natural killer cells, monocyte subtypes, and dendritic cells with cell frequencies and surface marker expressions compared between patients and controls, and correlated with standardized clinical motor and non-motor scores. Results: Overall, we found elevated frequencies and surface levels of markers related to migration (CCR2, CD11b) and phagocytosis (CD163) particularly on the elevated classical and intermediate monocytes in patients with Parkinson's disease for less than five years. This corresponded to a decrease of non-classical monocytes and dendritic cells. We observed an increased HLA-DR expression late in disease and sexual-dimorphism with TLR-4 expression decreased in women with PD but not in males. The disease-associated immune changes on TLR4, CCR2, and CD11b were correlated with non-motor symptoms such as olfaction or cognition. While many alterations were normalized at late disease stage, other changes remained, such as the increased HLA-DR and CD163 expressions. Conclusions: Our data highlight a role for peripheral CD163+ and migration-competent classical monocytes in Parkinson's disease. The study further suggests that the peripheral immune system is dynamically altered in Parkinson's disease stages and directly related to both non-motor symptoms and the sex-bias of the disease.

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Dopaminergic regulation of inflammation and immunity in Parkinson's disease: friend or foe?

Furgiuele,

Pereira,

Martini

et al. 2023

Clin & Trans Imm

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Parkinson's disease (PD) is a neurodegenerative disease affecting 7–10 million people worldwide. Currently, there is no treatment available to prevent or delay PD progression, partially due to the limited understanding of the pathological events which lead to the death of dopaminergic neurons in the substantia nigra in the brain, which is known to be the cause of PD symptoms. The current available treatments aim at compensating dopamine (DA) deficiency in the brain using its precursor levodopa, dopaminergic agonists and some indirect dopaminergic agents. The immune system is emerging as a critical player in PD. Therefore, immune‐based approaches have recently been proposed to be used as potential antiparkinsonian agents. It has been well‐known that dopaminergic pathways play a significant role in regulating immune responses in the brain. Although dopaminergic agents are the primary antiparkinsonian treatments, their immune regulatory effect has yet to be fully understood. The present review summarises the current available evidence of the immune regulatory effects of DA and its mimics and discusses dopaminergic agents as antiparkinsonian drugs. Based on the current understanding of their involvement in the regulation of neuroinflammation in PD, we propose that targeting immune pathways involved in PD pathology could offer a better treatment outcome for PD patients.

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The role of natural killer cells in Parkinson’s disease

Cited by 55 publications

References 134 publications

Monocyte markers correlate with immune and neuronal brain changes in REM sleep behavior disorder

Monocyte markers correlate with immune and neuronal brain changes in REM sleep behavior disorder

Changes in CD163+, CD11b+, and CCR2+ peripheral monocytes relate to Parkinson’s disease and cognition

Dopaminergic regulation of inflammation and immunity in Parkinson's disease: friend or foe?

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