Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2016

Open Access 01-12-2016 | Research

Infiltrating T lymphocytes reduce myeloid phagocytosis activity in synucleinopathy model

Authors: Annika Sommer, Tanja Fadler, Eva Dorfmeister, Anna-Carin Hoffmann, Wei Xiang, Beate Winner, Iryna Prots

Published in: Journal of Neuroinflammation | Issue 1/2016

Login to get access

Abstract

Background

Synucleinopathies comprise a group of neurodegenerative diseases associated with abnormal accumulation of α-synuclein. One of the key factors that contribute to the progression of synucleinopathies is neuroinflammation. However, the role of lymphocytes in synucleinopathies like Parkinson’s disease (PD) remains largely unclear.

Methods

To investigate how lymphocytes impact synucleinopathies, human wild-type α-synuclein (WTS) transgenic mice were crossed with mice lacking mature lymphocytes (Rag2−/−). In this in vivo model, we quantified α-synuclein aggregation in the substantia nigra (SN) and striatum and determined the numbers of innate and adaptive immune cells in the central nervous system (CNS). The activation state of resident and infiltrated CNS myeloid cells (M1 vs. M2) was further classified by gene and protein expression analyses. The impact of T and B lymphocytes on the phagocytic activity of microglia in the presence of α-synuclein aggregates was addressed in BV2 microglia in vitro.

Results

Compared to WTS+ Rag2+/+ mice, where T but not B lymphocytes infiltrated the CNS, decreased amounts of α-synuclein aggregates were found in WTS+ Rag2−/− mice devoid of mature lymphocytes. The presence of T lymphocytes did not alter the number of Iba1+ microglia but increased the frequency of the CD11b+ CD45hi population in the CNS, indicative of an increased number of infiltrated macrophages. Moreover, the M1 phenotype was more prominent in WTS+ Rag2+/+ mice, whereas the M2 activation state was dominating in the absence of lymphocytes in WTS+ Rag2−/− mice. In vitro, in the presence of T but not B lymphocytes, significantly less α-synuclein was phagocytosed by BV2 microglia, further supporting the prevalence of the M1 phenotype in the presence of T lymphocytes.

Conclusions

Peripheral T lymphocytes strongly contribute to increased α-synuclein pathology via modulation of CNS myeloid cell function. In the presence of T lymphocytes, microglia phagocytosis of aggregated α-synuclein is reduced, which increases the severity of synucleinopathy.
Appendix
Available only for authorised users
Literature
1.
Braak H et al. Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol Aging. 2003;24(2):197–211.CrossRefPubMed
2.
3.
4.
5.
Prinz M, Priller J. Microglia and brain macrophages in the molecular age: from origin to neuropsychiatric disease. Nat Rev Neurosci. 2014;15(5):300–12.CrossRefPubMed
6.
Streit WJ, Graeber MB, Kreutzberg GW. Functional plasticity of microglia: a review. Glia. 1988;1(5):301–7.CrossRefPubMed
7.
Kreutzberg GW. Microglia: a sensor for pathological events in the CNS. Trends Neurosci. 1996;19(8):312–8.CrossRefPubMed
8.
9.
10.
Boche D, Perry VH, Nicoll JA. Review: activation patterns of microglia and their identification in the human brain. Neuropathol Appl Neurobiol. 2013;39(1):3–18.CrossRefPubMed
11.
Saijo K, Glass CK. Microglial cell origin and phenotypes in health and disease. Nat Rev Immunol. 2011;11(11):775–87.CrossRefPubMed
12.
Shechter R et al. Infiltrating blood-derived macrophages are vital cells playing an anti-inflammatory role in recovery from spinal cord injury in mice. PLoS Med. 2009;6(7):e1000113.CrossRefPubMedPubMedCentral
13.
McGeer PL et al. Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson’s and Alzheimer’s disease brains. Neurology. 1988;38(8):1285–91.CrossRefPubMed
14.
Hirsch EC et al. The role of glial reaction and inflammation in Parkinson’s disease. Ann N Y Acad Sci. 2003;991:214–28.CrossRefPubMed
15.
Theodore S et al. Targeted overexpression of human alpha-synuclein triggers microglial activation and an adaptive immune response in a mouse model of Parkinson disease. J Neuropathol Exp Neurol. 2008;67(12):1149–58.CrossRefPubMedPubMedCentral
16.
Kannarkat GT, Boss JM, Tansey MG. The role of innate and adaptive immunity in Parkinson’s disease. J Parkinsons Dis. 2013;3(4):493–514.PubMedPubMedCentral
17.
Baba Y et al. Alterations of T-lymphocyte populations in Parkinson disease. Parkinsonism Relat Disord. 2005;11(8):493–8.CrossRefPubMed
18.
Brochard V et al. Infiltration of CD4+ lymphocytes into the brain contributes to neurodegeneration in a mouse model of Parkinson disease. J Clin Invest. 2009;119(1):182–92.PubMed
19.
Gonzalez H et al. Dopamine receptor D3 expressed on CD4+ T cells favors neurodegeneration of dopaminergic neurons during Parkinson’s disease. J Immunol. 2013;190(10):5048–56.CrossRefPubMed
20.
Hamza TH et al. Common genetic variation in the HLA region is associated with late-onset sporadic Parkinson’s disease. Nat Genet. 2010;42(9):781–5.CrossRefPubMedPubMedCentral
21.
Hisanaga K et al. Increase in peripheral CD4 bright + CD8 dull + T cells in Parkinson disease. Arch Neurol. 2001;58(10):1580–3.CrossRefPubMed
22.
Rockenstein E et al. Differential neuropathological alterations in transgenic mice expressing alpha-synuclein from the platelet-derived growth factor and Thy-1 promoters. J Neurosci Res. 2002;68(5):568–78.CrossRefPubMed
23.
Shinkai Y et al. RAG-2-deficient mice lack mature lymphocytes owing to inability to initiate V(D)J rearrangement. Cell. 1992;68(5):855–67.CrossRefPubMed
24.
Winner B et al. Human wild-type alpha-synuclein impairs neurogenesis. J Neuropathol Exp Neurol. 2004;63(11):1155–66.CrossRefPubMed
25.
Deusser J, et al. Serotonergic dysfunction in the A53T alpha-synuclein mouse model of Parkinson’s disease. J Neurochem. 2015;135(3):589–97.
26.
27.
Soltys Z et al. Morphology of reactive microglia in the injured cerebral cortex. Fractal analysis and complementary quantitative methods. J Neurosci Res. 2001;63(1):90–7.CrossRefPubMed
28.
29.
Sanchez-Guajardo V et al. Microglia acquire distinct activation profiles depending on the degree of alpha-synuclein neuropathology in a rAAV based model of Parkinson’s disease. PLoS One. 2010;5(1):e8784.CrossRefPubMedPubMedCentral
30.
31.
Prinz M et al. Heterogeneity of CNS myeloid cells and their roles in neurodegeneration. Nat Neurosci. 2011;14(10):1227–35.CrossRefPubMed
32.
33.
Hunot S, Hirsch EC. Neuroinflammatory processes in Parkinson’s disease. Ann Neurol. 2003;53 Suppl 3:S49–58. discussion S58-60.CrossRefPubMed
34.
Fleming SM et al. Early and progressive sensorimotor anomalies in mice overexpressing wild-type human alpha-synuclein. J Neurosci. 2004;24(42):9434–40.CrossRefPubMed
35.
Watson MB et al. Regionally-specific microglial activation in young mice over-expressing human wildtype alpha-synuclein. Exp Neurol. 2012;237(2):318–34.CrossRefPubMedPubMedCentral
36.
Kortekaas R et al. Blood-brain barrier dysfunction in parkinsonian midbrain in vivo. Ann Neurol. 2005;57(2):176–9.CrossRefPubMed
37.
38.
39.
Rezai-Zadeh K, Gate D, Town T. CNS infiltration of peripheral immune cells: D-Day for neurodegenerative disease? J Neuroimmune Pharmacol. 2009;4(4):462–75.CrossRefPubMedPubMedCentral
40.
Mildner A et al. Distinct and non-redundant roles of microglia and myeloid subsets in mouse models of Alzheimer’s disease. J Neurosci. 2011;31(31):11159–71.CrossRefPubMed
41.
London A, Cohen M, Schwartz M. Microglia and monocyte-derived macrophages: functionally distinct populations that act in concert in CNS plasticity and repair. Front Cell Neurosci. 2013;7:34.CrossRefPubMedPubMedCentral
42.
43.
Blasi E et al. Immortalization of murine microglial cells by a v-raf/v-myc carrying retrovirus. J Neuroimmunol. 1990;27(2-3):229–37.CrossRefPubMed
44.
Butovsky O et al. Identification of a unique TGF-beta-dependent molecular and functional signature in microglia. Nat Neurosci. 2014;17(1):131–43.CrossRefPubMed
45.
Mildner A et al. CCR2 + Ly-6Chi monocytes are crucial for the effector phase of autoimmunity in the central nervous system. Brain. 2009;132(Pt 9):2487–500.CrossRefPubMed
Metadata
Title
Infiltrating T lymphocytes reduce myeloid phagocytosis activity in synucleinopathy model
Authors
Annika Sommer
Tanja Fadler
Eva Dorfmeister
Anna-Carin Hoffmann
Wei Xiang
Beate Winner
Iryna Prots
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2016
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-016-0632-5

Other articles of this Issue 1/2016

Journal of Neuroinflammation 1/2016 Go to the issue

Research

Vascular-directed responses of microglia produced by methamphetamine exposure: indirect evidence that microglia are involved in vascular repair?

Research

VPAC1 receptor (Vipr1)-deficient mice exhibit ameliorated experimental autoimmune encephalomyelitis, with specific deficits in the effector stage

Research

Bullatine A stimulates spinal microglial dynorphin A expression to produce anti-hypersensitivity in a variety of rat pain models

Research

Circulating microRNAs as biomarkers for rituximab therapy, in neuromyelitis optica (NMO)

Research

Neuronal seipin knockout facilitates Aβ-induced neuroinflammation and neurotoxicity via reduction of PPARγ in hippocampus of mouse

Research

Pyrrolidine dithiocarbamate activates the Nrf2 pathway in astrocytes