Abstract
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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Abbreviations
- COX-2:
-
cyclooxygenase-2
- CUMS:
-
chronic unpredictable mild stress
- GFAP:
-
glial fibrillar acidic protein
- IFN-γ:
-
interferon gamma
- IL-1β:
-
interleukin1-β
- iNOS:
-
inducible nitric oxide synthase
- LPS:
-
lipopolysaccharide
- LFB:
-
luxol fast blue
- MCP-1:
-
monocytes chemotactic protein-1
- TLR4:
-
Toll-like receptor 4
- TNF-α:
-
tumor necrosis factor-α
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Acknowledgements
We thank N Farman and F Jaisser for MR reagents. This work was supported by the Institut National de la Santé et de la Recherche Médicale (Inserm), the Centre National de la Recherche Scientifique (CNRS), Université Marie et Pierre Curie (UPMC), Association France Parkinson (SV), Fondation de France (SV), Agence Nationale de la Recherche – ANR 2010 BLAN 1419 01 (EA). The Audinat lab is affiliated to Paris School of Neuroscience (ENP) and Tronche lab is a member of LabEX Biological Psychiatry.
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Carrillo-de Sauvage, M., Maatouk, L., Arnoux, I. et al. Potent and multiple regulatory actions of microglial glucocorticoid receptors during CNS inflammation. Cell Death Differ 20, 1546–1557 (2013). https://doi.org/10.1038/cdd.2013.108
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DOI: https://doi.org/10.1038/cdd.2013.108
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