Potent and multiple regulatory actions of microglial glucocorticoid receptors during CNS inflammation
Open accessAbstract
In CNS, glucocorticoids (GCs) activate both GC receptor (GR) and mineralocorticoid receptor (MR), whereas GR is widely expressed, the expression of MR is restricted. However, both are present in the microglia, the resident macrophages of the brain and their activation can lead to pro- or anti-inflammatory effects. We have therefore addressed the specific functions of GR in microglia. In mice lacking GR in macrophages/microglia and in the absence of modifications in MR expression, intraparenchymal injection of lipopolysaccharide (LPS) activating Toll-like receptor 4 signaling pathway resulted in exacerbated cellular lesion, neuronal and axonal damage. Global inhibition of GR by RU486 pre-treatment revealed that microglial GR is the principal mediator preventing neuronal degeneration triggered by lipopolysaccharide (LPS) and contributes with GRs of other cell types to the protection of non-neuronal cells. In vivo and in vitro data show GR functions in microglial differentiation, proliferation and motility. Interestingly, microglial GR also abolishes the LPS-induced delayed outward rectifier currents by downregulating Kv1.3 expression known to control microglia proliferation and oxygen radical production. Analysis of GR transcriptional function revealed its powerful negative control of pro-inflammatory effectors as well as upstream inflammatory activators. Finally, we analyzed the role of GR in chronic unpredictable mild stress and aging, both known to prime or sensitize microglia in vivo. We found that microglial GR suppresses rather than mediates the deleterious effects of stress or aging on neuronal survival. Overall, the results show that microglial GR acts on several key processes limiting pro-inflammatory actions of activated microglia.
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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 [116]
Microglia GR signaling suppresses rather than bolsters the priming effects of chronic stress on microglia reactivity to a subsequent intracerebral injection of LPS.
“In opposition, microglia GR signaling was recently found to suppress rather than bolster the priming effects of chronic stress on microglia reactivity to a subsequent intracerebral injection of LPS (116).”
From The HPA – Immune Axis and the Immunomodulatory Actions of Glucocorticoids in the Brain (2014) · cites this paper as [116]
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- Authors
- Carrillo-de Sauvage, M. Á., Maatouk, L., Arnoux, I., Pasco, M., Sanz Diez, A., Delahaye, M., Herrero, M. T., Newman, T. A., Calvo, C. F., Audinat, E., Tronche, F., & Vyas, S.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- Biomedical Research Networking Center on Neurodegenerative Diseases (ES)
- University of Southampton (GB)
- Corresponding author
- Vyas, S
- Venue
- Cell Death & Differentiation
- Published
- 2013-09-06
- Volume
- 20
- Issue
- 11
- Pages
- 1546-1557
- ISSN
- 1350-9047 (ISSN-L)
- 1476-5403
- PMC
- PMC3792430
- OpenAlex
- W2050527114
- Cited by
- 114
- References
- 58
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 13 · 2023: 11 · 2022: 12 · 2021: 16 · 2020: 10 · 2019: 8 · 2018: 9 · 2017: 8 · 2016: 6 · 2015: 7 · 2014: 6
- FWCI
- 3.55
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Cell Death and Differentiation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- ePrints Soton (University of Southampton) (submittedVersion)
- Repositori UJI (Universitat Jaume I) (submittedVersion, public-domain)
- Funders
- Agence Nationale de la Recherche
- Institut National de la Santé et de la Recherche Médicale
- Fondation de France
- Centre National de la Recherche Scientifique
- Association France Parkinson
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Keywords
- mineralocorticoid receptor, neuroinflammation, lipopolysaccharide, TLR4, neurodegeneration, axonal injury, microglial differentiation, microglial motility, Kv1.3 potassium channel, oxygen radical production, chronic unpredictable mild stress, aging, RU486
- MeSH terms
- Animals, Cell Movement, Central Nervous System, Inflammation, Lipopolysaccharides, Mice, Transgenic, Nerve Degeneration, Neurons, Receptors, Glucocorticoid, Signal Transduction, Microglia, Cell Growth Processes, Mice
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