Cited by 98Neuroinflammation and Neurodegeneration MechanismsParkinson's Disease Mechanisms and TreatmentsNuclear Receptors and Signaling

TLR9 activation via microglial glucocorticoid receptors contributes to degeneration of midbrain dopamine neurons

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Maatouk, Layal, Compagnion, Anne-Claire, Sauvage, Maria-Angeles Carrillo-de, Bemelmans, Alexis-Pierre, Leclere-Turbant, Sabrina, Cirotteau, Vincent, Tohme, Mira, Beke, Allen +7 more·2018·Nature Communications

Abstract

Inflammation is a characteristic feature of Parkinson’s disease (PD). We examined the role of TLR9 and its regulation by glucocorticoid receptors (GRs) in degeneration of substantia nigra dopamine neurons (DNs). TLR9 agonist, CpG-ODN, induced DN degeneration in mice lacking GR in microglia but not in controls. TLR9 deletion reduced DN loss in neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. GR regulates TLR9 activation during MPTP neurotoxicity as TLR9 antagonist suppressed increased DN loss in microglia/macrophage GR mutant mice. GR absence in microglia enhanced TLR9 translocation to endolysosomes and facilitated its cleavage leading to pro-inflammatory gene expression. GR-dependent TLR9 activation also triggered DN loss following intranigral injection of mitochondrial DNA. Finally, microglial GR sensitivity to A53T-alpha-synuclein induced DN degeneration as well as decreased microglial GR expression observed in SN of PD brain samples, all suggest that reduced microglial GR activity in SN can stimulate TLR9 activation and DN loss in PD pathology.

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  • CpG-DNA can induce neuronal degeneration in vivo only when glucocorticoid receptors are removed.

    “But CpG-DNA can induce neuronal degeneration in vivo only when glucocorticoid receptors (GRs) were removed”

    From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [320]

    The Results section reports that intranigral CpG ODN caused significant dopamine-neuron loss in mice lacking microglial/macrophage GR, but not a significant loss in control mice. The claim's “only when” is too absolute: the same section reports neuron loss after pharmacological GR inhibition with RU486, without receptor removal. The finding also concerns midbrain dopamine neurons, rather than neuronal degeneration generally. (LLM, conf=0.88)

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  • Decreased glucocorticoid receptors, observed in the brain of PD patients, enhanced activation of TLR9.

    “because decreased GRs, which is observed in the brain of PD patients, enhanced the activation of TLR9.320”

    From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [320]

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Authors
Maatouk, L., Compagnion, A.-C., Sauvage, M.-A. C.-D., Bemelmans, A.-P., Leclere-Turbant, S., Cirotteau, V., Tohme, M., Beke, A., Trichet, M., Bazin, V., Trawick, B. N., Ransohoff, R. M., Tronche, F., Manoury, B., & Vyas, S.
Affiliations
  • Centre National de la Recherche Scientifique (FR)
  • Université Paris-Sud (FR)
  • Sorbonne Université (FR)
Corresponding author
Vyas, Sheela
Venue
Nature Communications
Published
2018-06-22
Volume
9
Issue
1
Pages
2450-2450
ISSN
2041-1723 (ISSN-L)
OpenAlex
W2809111018
Cited by
95
References
63
Citations by year
2026: 16 · 2025: 6 · 2024: 15 · 2023: 7 · 2022: 18 · 2021: 18 · 2020: 6 · 2019: 9
FWCI
3.71
Type
journal article
Language
en
Open access
Locations
  • Nature Communications (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • HAL (submittedVersion, other-oa)
  • HAL (submittedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • Agence Nationale de la Recherche (ANR-13-BSV1-0013, ANR-10-LABX-0043)
  • Institut National de la Santé et de la Recherche Médicale
  • Fondation pour la Recherche Médicale (13-BSV1-0013-02)
  • Fondation de France
  • Association France Parkinson
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
Keywords
TLR9, glucocorticoid receptor, microglia, Parkinson's disease, substantia nigra, dopaminergic neuron loss, CpG oligodeoxynucleotides, MPTP-induced neurotoxicity, mitochondrial DNA, alpha-synuclein, neuroinflammation, pro-inflammatory gene expression
MeSH terms
Asparaginyl Endopeptidase, Aged, Aged, 80 and over, Animals, Cell Survival, Cysteine Endopeptidases, DNA, Mitochondrial, Female, Humans, Lysosomes, Male, Parkinson Disease, Receptors, Glucocorticoid, Substantia Nigra, Microglia, Mice, Knockout, Toll-Like Receptor 9, Mice, Dopaminergic Neurons

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