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Potent and multiple regulatory actions of microglial glucocorticoid receptors during CNS inflammation

Potent and multiple regulatory actions of microglial glucocorticoid receptors during CNS inflammation
Potent and multiple regulatory actions of microglial glucocorticoid receptors during CNS inflammation
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.
1350-9047
1546-1557
Carrillo-de Sauvage, M.A.
18b3cf9a-5416-4487-9a56-d07ae043d7bd
Maatouk, L.
d01ce541-5167-4070-a364-f46dfd681914
Arnoux, I.
e1ce2c8d-2ea3-4c9d-9538-d0d57854ec83
Pasco, M.
c8b04abb-09c9-4728-88cd-f6a56cc70ef4
Sanz Diez, A.
c91d8d26-5905-4144-99bd-f770dcad4900
Delahaye, M.
5126f2e8-cee4-4de1-9b39-23a117f17cfb
Herrero, M.T.
e9b4d396-1acc-43d5-a163-71034e9f77fb
Newman, T.A.
322290cb-2e9c-445d-a047-00b1bea39a25
Calvo, C.F.
2eafa3fc-9f32-4cc7-a302-d06aaed7bd20
Audinat, E.
abf37564-64b1-4744-8f66-419f4fa4b4cd
Tronche, F.
9cfc08fb-f7b0-4b38-84cd-c0a5a902e3a1
Vyas, S.
bcf36e04-bf96-4b4d-ae9c-0241cd76aa94
Carrillo-de Sauvage, M.A.
18b3cf9a-5416-4487-9a56-d07ae043d7bd
Maatouk, L.
d01ce541-5167-4070-a364-f46dfd681914
Arnoux, I.
e1ce2c8d-2ea3-4c9d-9538-d0d57854ec83
Pasco, M.
c8b04abb-09c9-4728-88cd-f6a56cc70ef4
Sanz Diez, A.
c91d8d26-5905-4144-99bd-f770dcad4900
Delahaye, M.
5126f2e8-cee4-4de1-9b39-23a117f17cfb
Herrero, M.T.
e9b4d396-1acc-43d5-a163-71034e9f77fb
Newman, T.A.
322290cb-2e9c-445d-a047-00b1bea39a25
Calvo, C.F.
2eafa3fc-9f32-4cc7-a302-d06aaed7bd20
Audinat, E.
abf37564-64b1-4744-8f66-419f4fa4b4cd
Tronche, F.
9cfc08fb-f7b0-4b38-84cd-c0a5a902e3a1
Vyas, S.
bcf36e04-bf96-4b4d-ae9c-0241cd76aa94

Carrillo-de Sauvage, M.A., Maatouk, L., Arnoux, I., Pasco, M., Sanz Diez, A., Delahaye, M., Herrero, M.T., Newman, T.A., Calvo, C.F., Audinat, E., Tronche, F. and Vyas, S. (2013) Potent and multiple regulatory actions of microglial glucocorticoid receptors during CNS inflammation. Cell Death and Differentiation, 20, 1546-1557. (doi:10.1038/cdd.2013.108). (PMID:24013726)

Record type: Article

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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e-pub ahead of print date: September 2013
Published date: November 2013
Organisations: Faculty of Medicine

Identifiers

Local EPrints ID: 358225
URI: https://eprints.soton.ac.uk/id/eprint/358225
ISSN: 1350-9047
PURE UUID: 4ffa4827-cfd7-46df-a8b1-d04ac84050cd
ORCID for T.A. Newman: ORCID iD orcid.org/0000-0002-3727-9258

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Date deposited: 09 Oct 2013 12:50
Last modified: 10 Jan 2019 01:37

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Contributors

Author: M.A. Carrillo-de Sauvage
Author: L. Maatouk
Author: I. Arnoux
Author: M. Pasco
Author: A. Sanz Diez
Author: M. Delahaye
Author: M.T. Herrero
Author: T.A. Newman ORCID iD
Author: C.F. Calvo
Author: E. Audinat
Author: F. Tronche
Author: S. Vyas

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