Microglial glucocorticoid receptors play a pivotal role in regulating dopaminergic neurodegeneration in parkinsonism
Open accessAbstract
Among the pathogenic processes contributing to dopaminergic neuron (DN) death in Parkinson disease (PD), evidence points to non-cell-autonomous mechanisms, particularly chronic inflammation mounted by activated microglia. Yet little is known about endogenous regulatory processes that determine microglial actions in pathological states. We examined the role of glucocorticoid receptors (GRs), activated by glucocorticoids released in response to stress and known to regulate inflammation, in DN survival. Overall GR level was decreased in substantia nigra of PD patients and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-intoxicated mice. GR changes, specifically in the microglia after MPTP treatment, revealed a rapid augmentation in the number of microglia displaying nuclear localization of GR. Mice with selective inactivation of the GR gene in macrophages/microglia (GR(LysMCre)) but not in DNs (GR(DATCre)) showed increased loss of DNs after MPTP intoxication. This DN loss in GR(LysMCre) mice was not prevented by corticosterone treatment, in contrast to the protection observed in control littermates. Moreover, absence of microglial GRs augmented microglial reactivity and led to their persistent activation. Analysis of inflammatory genes revealed an up-regulation of Toll-like receptors (TLRs) by MPTP treatment, particularly TLR9, the level of which was high in postmortem parkinsonian brains. The regulatory control of GR was reflected by higher expression of proinflammatory genes (e.g., TNF-α) with a concomitant decrease in anti-inflammatory genes (e.g., IL-1R2) in GR(LysMCre) mice. Indeed, in GR(LysMCre) mice, alterations in phosphorylated NF-κB levels indicated its protracted activation. Together, our data indicate that GR is important in curtailing microglial reactivity, and its deregulation in PD could lead to sustained inflammation-mediated DN injury.
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TLR9 is overexpressed in the substantia nigra and putamen of PD patients and in the striatum of a PD mouse model.
“TLR9 was found to be overexpressed in the substantia nigra and putamen of PD patients and in striatum of a PD mouse model,316”
From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [316]
Upon MPTP intoxication or intra-striatal injection of LPS, GRlysMCre mice exhibited greater neuronal loss, microglia reactivity, and expression of pro-inflammatory genes than age-matched controls.
“Upon MPTP intoxication (115) or intra-striatal injection of LPS (116), this strain exhibited greater neuronal loss, microglia reactivity, and expression of pro-inflammatory genes than age-matched controls.”
From The HPA – Immune Axis and the Immunomodulatory Actions of Glucocorticoids in the Brain (2014) · cites this paper as [115]
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- Authors
- Ros-Bernal, F., Hunot, S., Herrero, M. T., Parnadeau, S., Corvol, J.-C., Lu, L., Alvarez-Fischer, D., Carrillo-de Sauvage, M. A., Saurini, F., Coussieu, C., Kinugawa, K., Prigent, A., Höglinger, G., Hamon, M., Tronche, F., Hirsch, E. C., & Vyas, S.
- Affiliations
- Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche (UMR) 7224, F-75005 Paris, France;
- Centre National de la Recherche Scientifique (FR)
- Clinical and Experimental Neuroscience, Centro de Investigación Biomedica en Red de Enfermedades Neurodegenerativas (CIBERNED), School of Medicine, University of Murcia, 30100 Murcia, Spain;
- Université Pierre et Marie Curie–Paris 06, F-75252 Paris Cedex 5, France;
- Inserm (FR)
- Pitié-Salpêtrière Hospital (FR)
- Philipps University of Marburg (DE)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2011-04-05
- Volume
- 108
- Issue
- 16
- Pages
- 6632-6637
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3080980
- OpenAlex
- W2045465918
- Cited by
- 231
- References
- 33
- Citations by year
- 2026: 7 · 2025: 11 · 2024: 20 · 2023: 7 · 2022: 11 · 2021: 22 · 2020: 10 · 2019: 17 · 2018: 14 · 2017: 15 · 2016: 17 · 2015: 20 · 2014: 16 · 2013: 16 · 2012: 21
- FWCI
- 10.60
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- mediaTUM (Technical University of Munich) (submittedVersion)
- Funders
- Institut National de la Santé et de la Recherche Médicale
- Fondation de France
- Centre National de la Recherche Scientifique
- Ministerio de Ciencia e Innovación
- Université Pierre et Marie Curie
- 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
- glucocorticoid receptor, microglia, dopaminergic neuron loss, Parkinson's disease, MPTP-induced neurotoxicity, neuroinflammation, substantia nigra, TLR9, NF-κB signaling, corticosterone, microglial activation, TNF-α, IL1R2, non-cell autonomous neurodegeneration
- MeSH terms
- Aged, Aged, 80 and over, Animals, Cell Nucleus, Female, Humans, Inflammation, Male, Mice, Transgenic, Parkinson Disease, Receptors, Glucocorticoid, Substantia Nigra, Up-Regulation, Microglia, MPTP Poisoning, Toll-Like Receptors, Mice
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